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 http://onlinelibrary.wiley.com/doi/10.1002/

acn3.315/full

Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study

1.   Imis Dogan1,2,†

2.   Eugenie Tinnemann1,†,

3.   Sandro Romanzetti1,2

4.   Shahram Mirzazade1,2

5.   Ana S. Costa1,2,3

6.   Cornelius J. Werner1,2

7.   Stefan Heim2,4,5

8.   Kathrin Fedosov1,

9.   Stefanie Schulz1

10.               Dagmar Timmann6,

11.               Ilaria A. Giordano7,8

12.               Thomas Klockgether7,8

13.               Jörg B. Schulz1,2,4,‡ and

14.               Kathrin Reetz1,2,4,‡,*

 

Abstract

Objective

Friedreich's ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico-cerebellar dysfunctions underlying executive functioning in individuals with FRDA.

Methods

22 FRDA patients and 22 controls were clinically and neuropsychologically examined. Fifteen of each underwent structural and functional MRI using a verbal-fluency task with phonemic and semantic conditions. Gray (GM) and white matter (WM) alterations were assessed by means of voxel-based morphometry and diffusion-tensor imaging.

Results

The neuropsychological profile demonstrated deficits in verbal fluency, working memory and social cognition. Functional MRI data showed most pronounced group-differences in phonemic fluency with patients exhibiting enhanced activity in the cerebellum (VI, Crus I), fronto-insular, premotor and temporo-occipital regions. The semantic condition only revealed reduced activity in the anterior cerebellum; for overt speech, we found increased activity in the motor cortex. Functional connectivity-analysis showed higher co-activation within cerebellar and cortical regions, respectively, and impaired interregional coupling between the cerebellum and fronto-insular cortex for phonemic processing, which was also related to poorer task performance. GM reduction in FRDA was mainly found in lobule VI, whereas WM degeneration was more pronounced including brainstem, cerebellum, and cortex. Decreased cerebellar GM was associated with enhanced activity in the fronto-insular cortex, while loss of WM integrity may translate cortico-cerebellar pathway disruptions.

Interpretation

The pattern of increased neural response with both cerebellar and cortical involvement underlying executive functioning indicates functional reorganization driven by disease-related structural damage in FRDA.

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http://www.jogc.com/article/S1701-2163(16)39220-9/abstract

The New Genetic Inheritance: Mechanisms of Inheritance That Mendel Would Not Have Predicted With Sweet Peas

R. Douglas Wilson, MD, MSc, FRCSC, FACOG, FCCMG (Hon)

Department of Obstetrics and Gynaecology, Cumming School of Medicine, University of Calgary, Alberta Health Services, Calgary Zone, Calgary AB

DOI: http://dx.doi.org/10.1016/j.jogc.2016.04.091

showArticle Info

This brief and directed update is intended to provide readers with a better understanding of the “new genomics.” My aim is to help readers better understand the results of prenatal/fetal testing and to simplify interpretation of these results for their patients—at least on a basic level. Most importantly this update is intended to help readers know when they need assistance from a reproductive geneticist for making decisions and providing choices.

Abbreviations:

CNV (copy number variant), LCR (low copy repeats), ND (non-disjunction), SNP (single nucleotide polymorphism), TNR (tri-nucleotide repeat)

 

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http://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0464-5
Directions for new developments on statistical design and analysis of small population group trials

·        Ralf-Dieter HilgersEmail authorView ORCID ID profile,

·        Kit Roes,

·        Nigel Stallard and

·        for the IDeAl, Asterix and InSPiRe project groups

Abstract

Background

Most statistical design and analysis methods for clinical trials have been developed and evaluated where at least several hundreds of patients could be recruited. These methods may not be suitable to evaluate therapies if the sample size is unavoidably small, which is usually termed by small populations. The specific sample size cut off, where the standard methods fail, needs to be investigated. In this paper, the authors present their view on new developments for design and analysis of clinical trials in small population groups, where conventional statistical methods may be inappropriate, e.g., because of lack of power or poor adherence to asymptotic approximations due to sample size restrictions.

Method

Following the EMA/CHMP guideline on clinical trials in small populations, we consider directions for new developments in the area of statistical methodology for design and analysis of small population clinical trials. We relate the findings to the research activities of three projects, Asterix, IDeAl, and InSPiRe, which have received funding since 2013 within the FP7-HEALTH-2013-INNOVATION-1 framework of the EU. As not all aspects of the wide research area of small population clinical trials can be addressed, we focus on areas where we feel advances are needed and feasible.

Results

The general framework of the EMA/CHMP guideline on small population clinical trials stimulates a number of research areas. These serve as the basis for the three projects, Asterix, IDeAl, and InSPiRe, which use various approaches to develop new statistical methodology for design and analysis of small population clinical trials. Small population clinical trials refer to trials with a limited number of patients. Small populations may result form rare diseases or specific subtypes of more common diseases. New statistical methodology needs to be tailored to these specific situations.

Conclusion

The main results from the three projects will constitute a useful toolbox for improved design and analysis of small population clinical trials. They address various challenges presented by the EMA/CHMP guideline as well as recent discussions about extrapolation. There is a need for involvement of the patients’ perspective in the planning and conduct of small population clinical trials for a successful therapy evaluation.

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http://friedreichscientificnews.blogspot.com.es/2016/06/

oxidative-stress-in-neurological.html

Oxidative stress in neurological disease: Is it the cause, consequence, or trigger of a chronic progressive form?

J.A. Serra, E.R. Marschoff, R.O. Domínguez, Neurología (English Edition), Available online 17 June 2016, ISSN 2173-5808, doi:10.1016/j.nrleng.2016.06.003.

Systemic oxidative stress (OS) is basically an imbalance between the production of such oxi-dants as reactive oxygen species (ROS) and reactive nitrogenspecies (RNS), and the capacity to neutralise their detrimental effects through both exogenous (diet and medication) and endogenous antioxidants.
Systemic OS is increased in such entities as Alzheimer disease(AD), Parkinson’s disease (PD), amyotrophic lateral sclero-sis (ALS), chronic vascular encephalopathy (CVE), epilepsy,and Friedreich ataxia, among others. Reaching a balance between ROS andantioxidants may possibly diminish the risk of progression of these entities. Therefore, an emphasis should be made on the development of pharmacological studies aimed atminimising systemic OS.

 

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http://onlinelibrary.wiley.com/doi/10.1002/acn3.322/full

Deep sequencing of mitochondrial genomes reveals increased mutation load in Friedreich's ataxia

1.   Angela D. Bhalla1

2.   Alireza Khodadadi-Jamayran1

3.   Yanjie Li1

4.   David R. Lynch2and

5.   Marek Napierala1, Abstract

Objective

Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat expansion disorder caused by epigenetic silencing of the frataxin gene (FXN). Current research suggests that damage and variation of mitochondrial DNA (mtDNA) contribute to the molecular pathogenesis of FRDA. We sought to establish the extent of the mutation burden across the mitochondrial genome in FRDA cells and investigate the molecular mechanisms connecting FXN downregulation and the acquisition of mtDNA damage.

Methods

Damage and mutation load in mtDNA of a panel of FRDA and control fibroblasts were determined using qPCR and next-generation MiSeq sequencing, respectively. The capacity of FRDA and control cells to repair oxidative lesions in their mtDNA was measured using a quantitative DNA damage assay. Comprehensive RNA sequencing gene expression analyses were conducted to assess the status of DNA repair and metabolism genes in FRDA cells.

Results

Acute or prolonged downregulation of FXN expression resulted in a significant increase in mtDNA damage that translated to a significant elevation of mutation load in mtDNA. The predominant mutations identified throughout the mtDNA were C>T, G>A transitions (P = 0.007). Low FXN expression reduced capacity to repair oxidative damage in mtDNA. Downregulation of FXN expression strongly correlated (r = 0.73) with decreased levels of base excision repair (BER) DNA glycosylase NTHL1.

Interpretation

Downregulation of FXN expression in FRDA cells elevates mtDNA damage, increases mutation load of the mitochondrial genome, and diminishes DNA repair capacity. Progressive accumulation of mtDNA mutations in vulnerable FRDA patient cells reduces mitochondrial fitness ultimately leading to cell death.

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http://www.tcmonline.org/article/S1050-1738(16)30068-8/abstract?cc=y= 

Diagnosis and management of adult hereditary cardio-neuromuscular disorders: A model for the multidisciplinary care of complex genetic disorders

R. Brian Sommerville, MD

Margherita Guzzi Vincenti, BS

Kathleen Winborn, RN, BSN

Anne Casey, RN, BSN

Nathan O. Stitziel, M.D., Ph.D.

Anne M. Connolly, M.D.

Douglas L. Mann, M.D. correspondence email

Genetic disorders that disrupt the structure and function of the cardiovascular system and the peripheral nervous system are common enough to be encountered in routine cardiovascular practice. Although often these patients are diagnosed in childhood and come to the cardiologist fully characterized, some patients with hereditary neuromuscular disease may not manifest until adulthood and will present initially to the adult cardiologist for an evaluation of an abnormal ECG, unexplained syncope, LV hypertrophy and or a dilated cardiomyopathy of unknown cause. Cardiologists are often ill equipped to manage these patients due to lack of training and exposure as well as the complete absence of practice guidelines to aid in the diagnosis and management of these disorders. Here we review three key neuromuscular diseases that affect the cardiovascular system in adults (myotonic dystrophy type 1, Friedreich ataxia, and Emery-Dreifuss muscular dystrophy), with an emphasis on their clinical presentation, genetic and molecular pathogenesis, and recent important research on medical and interventional treatments. We also advocate the development of interdisciplinary cardio-neuromuscular clinics to optimize the care for these patients.

 

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http://europepmc.org/articles/PMC4877458

Obstructive Form of Hypertrophic Cardiomyopathy-Left Ventricular Outflow Tract Gradient: Novel Methods of Provocation, Monitoring of Biomarkers, and Recent Advances in the Treatment

Pawel Petkow Dimitrow * and Renata Rajtar-Salwa

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https://clinicaltrials.gov/ct2/show/NCT02797080?term=friedreich%27s+ataxia&rcv_d=14

·        Study Record Detail

STEADFAST Long-Term Safety Extension

 

This study is not yet open for participant recruitment. (see Contacts and Locations)

erified June 2016 by Horizon Pharma Ireland, Ltd., Dublin Ireland

Sponsor:

Horizon Pharma Ireland, Ltd., Dublin Ireland

Collaborator:

Friedreich's Ataxia Research Alliance

Information provided by (Responsible Party):

Horizon Pharma Ireland, Ltd., Dublin Ireland

ClinicalTrials.gov Identifier:

NCT02797080

First received: June 2, 2016

Last updated: June 7, 2016

Last verified: June 2016

History of Changes

·        Full Text View

·        Tabular View

·        No Study Results Posted

·        Disclaimer

·        How to Read a Study Record

https://clinicaltrials.gov/ct2/html/images/frame/triangle.gif  Purpose

The purpose of this long term extension study is to evaluate the long-term safety of ACTIMMUNE® in participants with Friedreich's Ataxia (FA).

 

Condition

Intervention

Phase

Friedreich's Ataxia

Drug: ACTIMMUNE®

Phase 3

 

Study Type:

Interventional

Study Design:

Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Official Title:

Long-Term Safety Extension Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich's Ataxia

 

Resource links provided by NLM:

 

Genetics Home Reference related topics: Friedreich 

ataxia VLDLR-associated cerebellar hypoplasia ataxia neuropathy 

spectrumautosomal

 recessive cerebellar ataxia type 1 childhood 

myocerebrohepatopathy 

spectrum deoxyguanosine kinase deficiencymitochondrial 

neurogastrointestinal encephalopathy disease 

myoclonic epilepsy 

myopathy sensory ataxia

MedlinePlus

related topics: Friedreich's Ataxia

Drug Information 

available for: Interferon Interferon Gamma-1b

Genetic and Rare Diseases Information Center resources: Friedreich Ataxia Spinocerebellar Ataxia

U.S. FDA Resources 

 

Further study details as provided by Horizon Pharma Ireland, Ltd., Dublin Ireland:

 

Primary Outcome Measures:

·        Number of Participants with Adverse Events [ Time Frame: Baseline up to 2 years ] [ Designated as safety issue: Yes ]

An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered an investigational product, whether or not the event is considered related to the investigational product. An AE is therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the investigational product.

 

 

Estimated Enrollment:

90

Study Start Date:

June 2016

Estimated Study Completion Date:

June 2018

Estimated Primary Completion Date:

June 2018 (Final data collection date for primary outcome measure)

 

Arms

Assigned Interventions

Experimental: ACTIMMUNE® (interferon γ-1b)

Drug: ACTIMMUNE®

ACTIMMUNE® will be administered three times per week by subcutaneous injection. The initial dose will be individualized for each participant and will be determined by the investigator, provided that the initial dose does not exceed the maximum tolerated dose in HZNP-ACT-302 (NCT02593773). The investigator may subsequently adjust the dose for any participant if deemed clinically appropriate, provided that the dose does not exceed 100 μg/m2.

Other Name: interferon γ-1b


Detailed Description:

This is a multi-center, open-label, long-term safety extension study of ACTIMMUNE® in the treatment of Friedreich's Ataxia (FA) in children and young adults. Participants who complete 26 weeks of treatment and the Week 28 Follow-Up Visit in HZNP-ACT-302 (NCT02593773) will be eligible to enter this long-term safety extension protocol. The Day 1 Visit of this study (HZNP-ACT-303) occurs on the same day as the Week 28 Follow-Up Visit for HZNP-ACT-302 (NCT02593773).Participants will be required to return for clinic visits at least every six months. The treatment duration is open-ended, and treatment will continue until ACTIMMUNE® is commercially available for the treatment of FA in the United States or until the Sponsor decides not to continue development for the treatment of FA.

https://clinicaltrials.gov/ct2/html/images/frame/triangle.gif  Eligibility

Ages Eligible for Study:  

11 Years to 27 Years   (Child, Adult)

Genders Eligible for Study:  

Both

Accepts Healthy Volunteers:  

No

Criteria

Inclusion Criteria:

·        Written informed consent and child assent, if applicable.

·        Completed 26 weeks of treatment and the Week 28 Follow-Up visit in Study HZNP-ACT-302 (NCT02593773). .

·        If female, the subject is not pregnant or lactating or intending to become pregnant during the study, or within 30 days after the last dose of study drug. Female subjects of child-bearing potential must have a negative urine pregnancy test result at Week 26 of Study HZNP-ACT-302 (NCT02593773) and agree to use a reliable method of contraception throughout the study and for 30 days after the last dose of study drug.

Exclusion Criteria:

·        If in the opinion of the Investigator, patients have a concomitant disease or condition that could interfere with the conduct of the study or potentially put the subject at unacceptable risk, the subject will be excluded from the study.

https://clinicaltrials.gov/ct2/html/images/frame/triangle.gif  Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies. 

Please refer to this study by its ClinicalTrials.gov identifier: NCT02797080

Contacts

Contact: Roxann Becco, RN

clinicaltrials@horizonpharma.com



Sponsors and Collaborators

Horizon Pharma Ireland, Ltd., Dublin Ireland

Friedreich's Ataxia Research Alliance

Investigators

Principal Investigator:

David Lynch, MD

Children's Hospital of

Philadelphia

https://clinicaltrials.gov/ct2/html/images/frame/triangle.gif  More Information

 

Responsible Party:

Horizon Pharma Ireland, Ltd., Dublin Ireland

ClinicalTrials.gov Identifier:

NCT02797080     History of Changes

Other Study ID Numbers:

HZNP-ACT-303 

Study First Received:

June 2, 2016

Last Updated:

June 7, 2016

Health Authority:

United States: Food and Drug Administration
United States: Institutional Review Board


Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland:

ACTIMMUNE
interferon y-1b


Additional relevant MeSH terms:

 

Ataxia
Friedreich Ataxia
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinocerebellar Degenerations
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Spinal Cord Diseases

Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Mitochondrial Diseases
Metabolic Diseases
Interferons
Interferon-gamma
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents


ClinicalTrials.gov processed this record on June 30, 2016

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http://www.sciencedirect.com/science/article/pii/

S0891584916302957 

Oxidative stress and altered lipid metabolism in Friedreich ataxia

·        Jordi Tamarit

·        Èlia Obis

·        Joaquim Ros

Abstract

Friedreich ataxia is a genetic disease caused by the deficiency of frataxin, a mitochondrial protein. Frataxin deficiency impacts in the cell physiology at several levels. One of them is oxidative stress with consequences in terms of protein dysfunctions and metabolic alterations. Among others, alterations in lipid metabolism have been observed in several models of the disease. In this review we summarize the current knowledge of the molecular basis of the disease, the relevance of oxidative stress and the therapeutic strategies based on reduction of mitochondrial reactive oxygen species production. Finally, we will focus the interest in alterations of lipid metabolism as a consequence of mitochondrial dysfunction and describe the therapeutic approaches based on targeting lipid metabolism.

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http://www.sciencedirect.com/science/article/pii/

S0035378716300017

Classifications of neurogenetic diseases: An increasingly complex problem

·        J.-M. Vallata

·        C. Goizetb

·        M. Tazirc

·        P. Couratiera

·        L. Magya

·        S. Mathisd, , 

Abstract

Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases. For this reason, our present proposals for updating and simplifying the classification of some of these conditions (Charcot–Marie–Tooth diseases, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, hereditary spastic ataxias, hereditary spastic paraplegias and hereditary spastic ataxias) are expounded here.

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http://www.sciencedirect.com/science/article/pii/

S0891584916300612 

PL-10 – NRF2 activators: how do they work and how advanced is their clinical use?

·        Antonio Cuadrado

·        Department of Biochemistry, Medical College, Autonomous University of Madrid, Madrid, Spain

Available online 7 June 2016

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http://www.nature.com/ejhg/journal/v24/n6/full/

ejhg2015271a.html

Responsible implementation of expanded carrier screening

Lidewij Henneman1, Pascal Borry2, Davit Chokoshvili2,3, Martina C Cornel1, Carla G van El1, Francesca Forzano4, Alison Hall5, Heidi C Howard6, Sandra Janssens3, Hülya Kayserili7, Phillis Lakeman8, Anneke Lucassen9, Sylvia A Metcalfe10, Lovro Vidmar11, Guido de Wert12, Wybo J Dondorp12 and Borut Peterlin11 on behalf of the European Society of Human Genetics (ESHG)

1.   1Department of Clinical Genetics, Section Community Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands

2.   2Centre for Biomedical Ethics and Law, University of Leuven, Leuven, Belgium

3.   3Centre for Medical Genetics Ghent, University Hospital Ghent, Ghent, Belgium

4.   4Medical Genetics Unit, Ospedali Galliera, Genova, Italy

5.   5PHG Foundation, Cambridge, UK

6.   6Centre for Research Ethics and Bioethics, Uppsala University, Uppsala, Sweden

7.   7Department of Medical Genetics, Koç University School of Medicine (KUSoM), Istanbul, Turkey

8.   8Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

9.   9Department of Clinical Ethics and Law (CELS), University of Southampton and Wessex Clinical Genetic Service, Southampton, UK

10.               10Murdoch Children's Research Institute and Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia

11.               11Clinical Institute of Medical Genetics, Ljubljana University Medical Centre, Ljubljana, Slovenia

12.               12Department of Health, Ethics & Society, Research Schools CAPHRI and GROW, Maastricht University, Maastricht, The Netherlands

Abstract

This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners’ personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.

 

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http://benthamscience.com/journals/current-drug-targets/article/142589/  
Histone deacetylase inhibitors modulating non-epigenetic players: The novel molecular targets for therapeutic intervention

 

Current Drug TargetsVolume 17 (E-pub ahead of print)

Author(s): 
Shabir Ahmad Ganai.

Affiliation: Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar-190006, Jammu & Kashmir India

Abstract

Histone deacetylases (HDACs) play a crucial role in regulating the expression and activity of myriad of proteins involved in tumour onset and progression. HDAC activity results in a non-permissive chromatin conformation by erasing acetyl moiety from histone substrates culminating in transcriptional repression of those genes having significant role in tumourigenesis. Apart from histones, HDACs deacetylate a variety of non-histone proteins including transcription factors involved in controlling cell growth, differentiation and apoptosis. Histone deacetylase inhibitors (HDACi) are small-molecules restraining HDACs and hence modulating their biological activity. Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor- kappaB (NF-кB), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer. The present article explores the therapeutic role of HDACi with special emphasis on modulation of clinically relevant non-histone molecular targets. Extensive details regarding the non-histone proteins and their deregulation in disease states have also been provided. Moreover, the underlying molecular mechanism triggered by HDACi to overcome disease states by modulating the predefined targets has also been illuminated. The article strongly suggests the promising use of HDACi in therapeutic intervention against complications arising due to non-histone protein deregulation.

 

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http://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0444-9


Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers

·        T. Morel

·        S. Aymé,

·        D. Cassiman,

·        S. Simoens,

·        M. Morgan and

·        M. Vandebr

Abstract

Background

Rare disease patients and caregivers face uncommon, serious, debilitating conditions often characterised by poor prognosis and limited treatment options. This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.

Methods

A mixed-methods survey with patients and caregivers was conducted in the United Kingdom across a range of rare diseases. Discrete-choice experiments that compared hypothetical treatment profiles of benefits and risks were used to measure respondent preferences across a set of seven attributes related to health outcomes, safety, and process of care. Bespoke questions on current disease management and the joint use of the 12-item WHODAS 2.0 questionnaire and of two Likert scales capturing self- and proxy-assessed disease-induced threat to life and impairment were implemented to describe disease context. Additionally, qualitative insights on the definitions of value and risk were collected from respondents.

Results

Final study sample included 721 patients and 152 informal caregivers, across 52 rare diseases. When choosing between hypothetical novel treatments for rare diseases, respondents attributed most importance to drug response, risk of serious side effects, and the ability to conduct usual activities while on treatment. In contrast, attributes related to treatment modalities were the least important. Respondents expressed a willingness to accept risks in hopes of finding some benefit, such as a higher chance of drug response or greater health improvement potential. Increasing disease severity, impairment or disability, and the lack of effective therapeutic options were shown to raise significantly the willingness to gain benefit through increased risk.

Conclusions

This is the first study performing a quantitative discrete choice experiment amongst patients and caregivers across 52 rare conditions. It enables a more detailed understanding of the relationship between disease context, treatment attributes and the degree of risk respondents are willing to take to gain a specific degree of benefit. Researchers of novel therapeutics for rare diseases should be encouraged to invest in preference elicitation studies to generate rigorous patient evidence and specific regulatory guidance should be issued to acknowledge their importance and their use in marketing authorisations.

 

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http://www.samj.org.za/index.php/samj/article/view/10989 

The hereditary ataxias: Where are we now? Four decades of local research

D C Smith, L J Greenberg, A Bryer

Abstract

 

The hereditary ataxias have been studied at the University of Cape Town for more than 40 years, following from initial clinical investigations by Beighton and colleagues in the early 1970s. This group of inherited disorders is characterised by progressive neurodegeneration and associated symptoms, including the inability to coordinate movement. Following initial local and international linkage studies, and the discovery of the genes responsible for the key dominant and recessive inherited ataxias in the 1990s, a local molecular testing service was established at Groote Schuur Hospital. More than 1 600 individuals have been referred through this testing service (now offered by the National Health Laboratory Service), leading to the molecular diagnosis of 253 families with spinocerebellar ataxia types 1, 2, 3, 6 or 7, and 30 families with Friedreich’s ataxia. This is likely to be an under-representation of the number of South Africans affected with hereditary ataxia, and future research efforts will focus on increasing the awareness of this group of disorders, both locally and throughout the rest of Africa. Next-generation technologies will be beneficial in identifying additional genes underlying inherited ataxia in indigenous patients to enable more appropriate management and treatment of individuals with molecularly undiagnosed forms of the disease.

 

 

Authors' affiliations

D C Smith, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town; and Division of Neurology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa

L J Greenberg, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa

A Bryer, Division of Neurology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa

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The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy

·        Arnulf H. Koeppenabc, , 

·        Alyssa B. Beckera

·        Paul J. Feusteld

·        Benjamin B. Gelmane

·        Joseph E. Mazurkiewiczd

Astract

Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling. The principal components of ICD are fascia adherens junctions (FAJ), desmosomes, and gap junctions. Frataxin deficiency in FRDA may cause improper assembly of ICD early in life, making hearts vulnerable to mechanical stress in childhood and adolescence. We studied the ICD in the myocardium of left ventricular wall (LVW), right ventricular wall, and ventricular septum in 18 genetically confirmed FRDA patients (age of death, 10 to 87 years) and 12 normal controls (age of death, 13 to 69 years). In cases with juvenile onset, electron microscopy and immunohistochemistry of N-cadherin and vinculin, two abundant FAJ proteins, showed enlargement of ICD, discontinuity, and hyperconvolution. Reaction product of the desmosomal protein desmoglein 2 was similar. The distribution of the gap junction protein connexin 43 at ICD was also irregular and displayed abnormal lateralization to the plasma membranes of cardiomyocytes. Confocal immunofluorescence microscopy of α-actinin, affinity fluorescence microscopy of actin with rhodamine-labeled phalloidin, and electron microscopy, revealed the principal integrity of sarcomeres of the myocardium in FRDA. In two late-onset long-surviving FRDA patients (ages 79 and 87), clinical cardiomyopathy was absent, and ICD were normal. The described observations in patients with a broad range of disease onset and duration allow us to conclude that faulty assembly of ICD interferes with proper end-to-end adhesion of cardiomyocytes of the growing heart and contributes to the pathogenesis of FRDA cardiomyopathy.


Journal of the Neurological Sciences

Volume 367, 15 August 2016, Pages 171–176

Cover image

The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy

·        Arnulf H. Koeppenabc, , 

·        Alyssa B. Beckera

·        Paul J. Feusteld

·        Benjamin B. Gelmane

·        Joseph E. Mazurkiewiczd

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doi:10.1016/j.jns.2016.06.006

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Highlights

The most frequent cause of death in Friedreich ataxia is cardiomyopathy.

Abnormal intercalated discs contribute to Friedreich cardiomyopathy.

Intercalated discs and gap junctions are normal in long-surviving patients.


Abstract

Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling. The principal components of ICD are fascia adherens junctions (FAJ), desmosomes, and gap junctions. Frataxin deficiency in FRDA may cause improper assembly of ICD early in life, making hearts vulnerable to mechanical stress in childhood and adolescence. We studied the ICD in the myocardium of left ventricular wall (LVW), right ventricular wall, and ventricular septum in 18 genetically confirmed FRDA patients (age of death, 10 to 87 years) and 12 normal controls (age of death, 13 to 69 years). In cases with juvenile onset, electron microscopy and immunohistochemistry of N-cadherin and vinculin, two abundant FAJ proteins, showed enlargement of ICD, discontinuity, and hyperconvolution. Reaction product of the desmosomal protein desmoglein 2 was similar. The distribution of the gap junction protein connexin 43 at ICD was also irregular and displayed abnormal lateralization to the plasma membranes of cardiomyocytes. Confocal immunofluorescence microscopy of α-actinin, affinity fluorescence microscopy of actin with rhodamine-labeled phalloidin, and electron microscopy, revealed the principal integrity of sarcomeres of the myocardium in FRDA. In two late-onset long-surviving FRDA patients (ages 79 and 87), clinical cardiomyopathy was absent, and ICD were normal. The described observations in patients with a broad range of disease onset and duration allow us to conclude that faulty assembly of ICD interferes with proper end-to-end adhesion of cardiomyocytes of the growing heart and contributes to the pathogenesis of FRDA cardiomyopathy.


Journal of the Neurological Sciences

Volume 367, 15 August 2016, Pages 171–176

Cover image

The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy

·        Arnulf H. Koeppenabc, , 

·        Alyssa B. Beckera

·        Paul J. Feusteld

·        Benjamin B. Gelmane

·        Joseph E. Mazurkiewiczd

 Show more

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doi:10.1016/j.jns.2016.06.006

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-------------------------------------------------------------------------

http://www.sciencedirect.com/science/article/pii/

S0022510X16303379

The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy

·        Arnulf H. Koeppenabc, , 

·        Alyssa B. Beckera

·        Paul J. Feusteld

·        Benjamin B. Gelmane

·        Joseph E. Mazurkiewiczd

 

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling. The principal components of ICD are fascia adherens junctions (FAJ), desmosomes, and gap junctions. Frataxin deficiency in FRDA may cause improper assembly of ICD early in life, making hearts vulnerable to mechanical stress in childhood and adolescence. We studied the ICD in the myocardium of left ventricular wall (LVW), right ventricular wall, and ventricular septum in 18 genetically confirmed FRDA patients (age of death, 10 to 87 years) and 12 normal controls (age of death, 13 to 69 years). In cases with juvenile onset, electron microscopy and immunohistochemistry of N-cadherin and vinculin, two abundant FAJ proteins, showed enlargement of ICD, discontinuity, and hyperconvolution. Reaction product of the desmosomal protein desmoglein 2 was similar. The distribution of the gap junction protein connexin 43 at ICD was also irregular and displayed abnormal lateralization to the plasma membranes of cardiomyocytes. Confocal immunofluorescence microscopy of α-actinin, affinity fluorescence microscopy of actin with rhodamine-labeled phalloidin, and electron microscopy, revealed the principal integrity of sarcomeres of the myocardium in FRDA. In two late-onset long-surviving FRDA patients (ages 79 and 87), clinical cardiomyopathy was absent, and ICD were normal. The described observations in patients with a broad range of disease onset and duration allow us to conclude that faulty assembly of ICD interferes with proper end-to-end adhesion of cardiomyocytes of the growing heart and contributes to the pathogenesis of FRDA cardiomyopathy.

 

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https://www.ipscell.com/2016/06/10-top-patient-groups-oppose-regrow-act-that-would-gut-stem-cell-oversight/

10 top patient groups oppose REGROW Act that would gut stem cell oversight

Posted on June 1, 2016

michael j. fox foundationThe REGROW Act would drastically weaken FDA regulation of experimental stem cell therapies. I’ve criticized it in numerous posts (see those here) for its radical ideas that would put patients and the stem cell field at risk.

I’m not the only one concerned about it as both ARM and ISSCR oppose it too.

Now 10 top patient advocacy groups together

announced their opposition to it as well.  The patient groups that include the Michael J. Fox Foundation (see complete list at the bottom of this email) cited their concerns over risks to patients from the bill in a letter to Senator Mark Kirk, who is the main sponsor.

I commend these patient groups for this move and I wholly agree with their sentiment that existing FDA mechanism are a better way to proceed. For instance, instead of REGROW we should be pressuring the FDA to use its Breakthrough designation and Fast Track review for stem cells more readily.

Patient Groups Opposing REGROW

§  Cystic Fibrosis Foundation

§  Friedreich’s Ataxia Research Alliance

§  Friends of Cancer Research

§  Global Genes

§  Michael J. Fox Foundation for Parkinson’s Research

§  Myotonic Dystrophy Foundation

§  National MS Society

§  National Organization for Rare Disorders

§  National Patient Advocate Foundation

§  Prevent Cancer Foundation

 

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http://www.bioportfolio.com/news/article/2730254/US-FDA-Grants-Orphan-Drug-Designation-for-Retrotopes-RT001-in-the-Treatment.html

US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Friedreich's Ataxia

LOS ALTOS, CA -- (Marketwired) -- 06/01/16 -- Retrotope announced today that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development granted orphan drug designation for its stabilized fatty acid drug (RT001) for the treatment of Friedreich's ataxia (FA). This follows the recent announcement that RT001 was well tolerated with no serious adverse events or dose limiting toxicities in the first cohort of its Phase 1/2 clinical trial in FA patients.

Related Biotechnology, Pharmaceutical and Healthcare News

·        Retrotope Advances RT001 in Clinical Trials to Treat Friedreich's ataxia

·        Portage's Biohaven Orphan Drug Designation Request Granted for Spinocerebellar Ataxia

·        FDA grants DelMar second orphan designation for VAL-083

·        FDA grants orphan drug designation to DelMar’s ovarian cancer drug

·        U.S. FDA Grants Orphan Drug Designation to Pluristemb

FA is a debilitating, life-shortening neuro-degenerative disorder that affects approximately 5,000 people in the United States, and over 20,000 people worldwide. A progressive loss of coordination and muscle strength leads to motor incapacitation, the full-time use of a wheelchair, and ultimately early death, typically from cardiomyopathy. RT001 is a chemically stabilized form of a natural fatty acid that confers resistance to lipid peroxidation in mitochondrial and cellular membranes via a novel mechanism. There is currently no approved treatment for FA.

Robert Molinari, Ph.D., CEO of Retrotope, commented:"We are pleased that FDA has granted us orphan status with the benefits that such status accrues to our program. We have been fortunate to have had the support of the Friedreich's Ataxia Research Alliance (FARA) since the inception of our clinical program for RT001. We are also grateful to the patients and clinicians who are participating in our first-in-human clinical trial of RT001 for this devastating condition."

Jennifer Farmer, MS, CGC, Executive Director of the Friedreich's Ataxia Research Alliance (FARA), said,"FARA is pleased to continue our support of Retrotope. We utilized our Patient Registry to help recruit patients for the Phase 1 that is now fully enrolled. We look forward to a continued partnership as Retrotope's clinical development advances to further evaluate their new approach to treating FA. We are excited by the potential of RT001 and hope this new drug benefits FA patients."

Retrotope is conducting a study at two sites: the University of South Florida Ataxia Research Center and the Collaborative NeuroSciences Network in Long Beach, CA. The trial has recently been fully enrolled. For more information on this study, please visit: 

https://clinicaltrials.gov/ct2/show/NCT02445794.

About RT001 
Retrotope has discovered that lipid peroxidation, the free-radical degradation of lipids in mitochondrial and cellular membranes, may be causative of a wide range of degenerative diseases. Free radicals attack and degrade polyunsaturated fats (PUFAs) that are essential membrane components. Retrotope and others have shown that the degradation products of these fats create toxic cascades that have been associated with many illnesses of degeneration, and particularly ones with mitochondrial lipid damage. RT001 is a patented, orally available modified fatty-acid therapeutic that stabilizes ("fireproofs") mitochondrial and cellular membranes against attack and restores cellular health.

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http://www.firstwordpharma.com/node/1387626

#axzz4ALaSwUhL 

Epoetin Alpha Improves Upper-Limb Dexterity in Patients With Friedreich’s Ataxia: Presented at EAN

May 31st, 2016

y Chris Berrie

COPENHAGEN, Denmark -- May 31, 2016 -- Epoetin alpha does not modify frataxin levels or improve physical performance in patients with the debilitating, degenerative neuromuscular disorder known as Friedreich’s ataxia, although it progressively ameliorates upper-limb dexterity compared with placebo, according to results presented at the 2nd Congress of the European Academy of Neurology (EAN)

Individuals with Friedreich’s ataxia have 2 mutated or abnormal copies of the FXN gene. The mutation reduces FXN mRNA levels, which, in turn, reduces frataxin protein levels by 36% compared with control subjects, explained lead author Francesco Saccà, MD, ‘Federico II’ University of Naples, Naples, Italy, speaking here on May 28 on behalf of the FriEMax group.

Erythropoietin, a glycoprotein hormone and cytokine, had been investigated in Friedreich’s ataxia, although its ability to increase frataxin levels in these patients had not been consistent.

In the current study, “unfortunately, there was no effect of epoetin alpha on frataxin levels,” Dr. Saccà noted.

While epoetin alpha had no effect on cardiopulmonary exercise-test parameters, and did not increase frataxin in this study, Dr. Saccà pointed out that “it ameliorates upper-limb dexterity after 24 and 48 weeks of treatment, and this is the first demonstration that some drug has some effect on Friedreich’s ataxia, apart from biochemical endpoints.”

The researchers designed their study to test the effects of high-dose epoetin alpha, the short-term recombinant human erythropoietin, on physical performance of patients with Friedreich’s ataxia. They monitored maximum oxygen uptake (VO2max) in the cardiopulmonary exercise test as the primary endpoint, along with various secondary endpoints, including levels of frataxin protein in peripheral blood mononuclear cells.

Following screening, the investigators randomised patients with a molecular diagnosis of Friedreich’s ataxia to receive either placebo (n = 28) or epoetin alpha 1,200 IU/kg SC (n = 28) every 12 weeks, to 36 weeks, with a further 12 weeks of follow-up.

There was a small increase from baseline in VO2max for both the placebo and active-treatment groups at 24 weeks (0.4 vs 1.6 mL O2/kg/min) and 48 weeks (1.9 vs 1.9 mL O2/kg/min), with epoetin alpha demonstrating no significant benefit.

Similarly, epoetin alpha demonstrated no significant benefit on the Scale for Assessment and Rating of Ataxia (SARA) and the Left Ventricular (LV) Mass Index, although both tools showed trends for improvement with epoetin alpha over placebo (48 weeks: SARA, -0.71; LV Mass Index, -5.6 g).

In the 9-Hole Peg Test, epoetin alpha significantly promoted improved upper-limb dexterity over placebo at both 24 weeks (difference over placebo: -11.3 seconds; P = .015) and 48 weeks (-17.24 seconds; P = .018).

There was no significant difference between placebo and epoetin alpha for all adverse events (53 vs 74 events). “None of the adverse events were significantly associated with the study drug,” Dr Saccà added. There was, however, higher frequency of flu-like syndrome with the study drug (6 vs 12 incidences).

Patient baseline characteristics were similar between the 2 groups, with patients being 52% male and having a mean age of 35.8 years (19.3 years at disease onset). Baseline VO2max was 14.0 mL O2/kg/min.

Friedreich’s ataxia manifests in initial symptoms of poor coordination, such as gait disturbance, and can eventually lead to scoliosis, heart disease, and diabetes. The disease is caused by a, homozygous GAA expansion in the first intron of the FXN gene.

To date, there is no therapy available.

[Presentation title: Long-Term Effect of Epoetin Alfa on Clinical and Biochemical Markers in Friedreich’s Ataxia. Abstract O1116]

-------------------------------------------------

http://science.sciencemag.org/content/352/6289/1059.full

Paying for future success in gene therapy

1.  Stuart H. Orkin1

2.  Philip Reilly2

+ Author Affiliations

1.   Email: stuart_orkin@dfci.harvard.eduphilip@thirdrockventures.com

Science  27 May 2016:
Vol. 352, Issue 6289, pp. 1059-1061
DOI: 10.1126/science.aaf4770

 

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http://rsta.royalsocietypublishing.org/content/374/

2067/20160020

Uncovering brain–heart information through advanced signal and image processing

Gaetano Valenza, Nicola Toschi, Riccardo Barbieri

Abstract

Through their dynamical interplay, the brain and the heart ensure fundamental homeostasis and mediate a number of physiological functions as well as their disease-related aberrations. Although a vast number of ad hoc analytical and computational tools have been recently applied to the non-invasive characterization of brain and heart dynamic functioning, little attention has been devoted to combining information to unveil the interactions between these two physiological systems. This theme issue collects contributions from leading experts dealing with the development of advanced analytical and computational tools in the field of biomedical signal and image processing. It includes perspectives on recent advances in 7 T magnetic resonance imaging as well as electroencephalogram, electrocardiogram and cerebrovascular flow processing, with the specific aim of elucidating methods to uncover novel biological and physiological correlates of brain–heart physiology and physiopathology.

Over the past few years, there has been increasing evidence for the potential clinical implications of dysfunctional brain–heart interactions. For instance, cerebrovascular accidents and transient ischaemic attacks (transient episodes of neurological dysfunction caused by the loss of blood flow) are frequently caused by cardiac arrhythmias [1], and atrial fibrillation may also result in cognitive disorders [2], even in the absence of manifest stroke [36]. On the other hand, brain disorders, including stroke, epilepsy and others thought to be secondary to environmental stress (e.g. panic disorders and emotional distress), may lead to cardiovascular disorders and have been shown to result in cardiac arrhythmias both experimentally and clinically [7]. A recent article in Scientific American (‘A new idea for treating Alzheimer's’) 8begins with the following sentence: ‘If it's good for the heart, it could also be good for the neurons, astrocytes and oligodendrocytes, cells that make up the main items on the brain's parts list’, suggesting that Alzheimer's disease may be a candidate for combined brain–heart therapeutic approaches. Furthermore, a wide variety of changes in the electrocardiogram, mainly referring to arrhythmias and repolarization, is often observed in the context of neurological disease [9].

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http://www.sciencedirect.com/science/article/pii/

S0223523416304457

Inside HDACs with more selective HDAC inhibitors

·        Joëlle Rocheac

·        Philippe Bertrandbc, , 

Highlights

Histone deacetylases (HDACs) are epigenetic regulators of protein acetylation.

Abnormal expression of HDACs is involved in human diseases such as cancers.

HDAC inhibitors are used to renormalize protein acetylation in human diseases.

HDAC inhibitor design is mostly oriented toward HDAC selectivity for class members.

Other structural modifications include multi-target activities or imaging modalities.


Abstract

Inhibitors of histone deacetylases (HDACs) are nowadays part of the therapeutic arsenal mainly against cancers, with four compounds approved by the Food and Drug Administration. During the last five years, several groups have made continuous efforts to improve this class of compounds, designing more selective compounds or compounds with multiple capacities. After a survey of the HDAC biology and structures, this review summarizes the results of the chemists working in this field, and highlights when possible the behavior of the molecules inside their targets.

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http://www.nature.com/cddis/journal/v7/n5/full/

cddis2016111a.html

'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia'

R Abeti1,5, M H Parkinson1, I P Hargreaves2, P R Angelova3, C Sandi4,6, M A Pook4, P Giunti1,7 and A Y Abramov3,7

1.   1Ataxia Centre, Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, UK

2.   2National Hospital, Neurometabolic Unit, London UK

3.   3Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, UK

4.   4Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health & Life Sciences, and Synthetic Biology Theme, Institute of Environment, Health & Societies, Brunel University London, Uxbridge, UK

 

Abstract

Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure.

 

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http://www.prweb.com/releases/2016/05/

prweb13439929.htm 

Jupiter Orphan Therapeutics, Inc. (JOT) today announced that world renowned scientist David Sinclair, Ph.D. joined JOT as Co-Chairman of its Scientific Advisory Board (SAB).

News Image

David Sinclair Ph.D.

"JOT's JOTROL product opens up the possibility that resveratrol will finally realize its potential to revolutionize human health.”

JUPITER, FLORIDA (PRWEB) MAY 25, 2016

Jupiter Orphan Therapeutics, Inc. (JOT) today announced that world renowned scientist David Sinclair, Ph.D. joined JOT as Co-Chairman of its Scientific Advisory Board (SAB).

“This is a fantastic addition to our company and Dr. Sinclair’s knowledge, network and reputation is very valuable to a small company like Jupiter Orphan Therapeutics” stated JOT CEO, Christer Rosén.

Dr. Sinclair stated “I am excited about being able to work with JOT to bring drugs to patients who are waiting for a solution to their rare disease. JOTROL opens up the possibility that resveratrol will finally realize its potential to revolutionize human health.”

Dr. Sinclair was contacted by his fellow scientists, Prof Martin Delatycki from Murdoch Childrens Research Institute, Australia (MCRI), who informed him of the resveratrol JOTROL product that was developed by JOT. JOT has a global license from MCRI regarding developing JOT101, a product for treatment of Friedreich’s ataxia.

Dr. Sinclair, who is one of the leading scientists in the world regarding resveratrol’s benefit in various disease areas, expressed his enthusiasm of the test results achieved with JOTROL and immediately accepted a position as Co-Chairman of the JOT Scientific Advisory Board.

David Sinclair, Ph.D. is the Co-Chairman of the JOT Scientific Advisory Board at Jupiter Orphan Therapeutics. He is currently the Co-Director of the Paul F. Glenn Center for the Biology of Aging as well as the Professor of Genetics at Harvard Medical School. Dr. Sinclair has co-founded eight biotechnology companies, four of which have gone public, including Sirtris Pharmaceuticals which was sold to GlaxoSmithKline for $720M. He has 170 publications and 40 patents. Dr. Sinclair co-discovered Sirtuin activating compounds (STACs) such as resveratrol and SRT2104. Dr. Sinclair was named one of Time Magazine’s “Top 100 Most Influential People in the World” in 2014.

Jupiter Orphan Pharmaceuticals, Inc., http://www.jupiterorphan.com, was formed to address rare diseases caused by, or related to, single gene deficiencies.

Visit http://www.jupiterorphan.com for additional company information.

Media contact:

Christer Rosén, Jupiter Orphan Therapeutics - +1 561 308-7780 
c.rosen(at)jupiterorphan(dot)com

 

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http://friedreichscientificnews.blogspot.com.es

/2016/05/longitudinal-strain-bulls-eye-plot.html

Longitudinal strain bull's eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy.

Dan Liu, Kai Hu, Peter Nordbeck, Georg Ertl, Stefan Störk and Frank Weidemann. European Journal of Medical Research 201621:21 DOI: 10.1186/s40001-016-0216-y

Friedreich’s ataxia: Besides the neurologic manifestation, cardiac involvement and endocrine involvement are also frequent. A concentric LVH with an end-diastolic wall thickness of less than 15 mm is the usual echocardiographic feature. Around 40 % of FA patients show concentric remodeling, 35 % show concentric hypertrophy and only 5 % display an eccentric hypertrophy. Global systolic function and diastolic function remain normal in most FA patients, and only end-stage FA patients develop reduced EF with global hypokinesia and slightly dilated LV chamber.

https://static-content.springer.com/image/art%3A10.1186%2Fs40001-016-0216-y/MediaObjects/40001_2016_216_Fig7_HTML.jpg

Electrocardiographic abnormalities (ST-T changes) are often the earliest sign of FA cardiomyopathy. At this early stage, echocardiography results are usually normal and the longitudinal strain bull’s eye plot is similar pattern as healthy subjects (Fig. 7a). In FA patients with concentric LVH and normal EF, the bull’s eye plot pattern presents with a mildly reduced average global strain (Fig. 7b). Myocardial fibrosis develops gradually, leading to LV wall thinning and LV dilatation during the disease progression, while EF remains preserved for a long time until the end-stage of the disease. Of note, the LV wall thinning appears to be diffuse in FA cardiomyopathy, which is different from the typical findings in Fabry cardiomyopathy. The bull’s eye plot shows significantly reduced average global longitudinal strain when LVEF is reduced (Fig. 7c).

CMRI with LE imaging provides evidence of fibrosis in the advanced stage of this disease, suggesting that fibrosis might be associated with subsequent myocardial dysfunction.

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http://www.sciencedirect.com/science/article/pii/

S1568786416300994

Role of XPD in cellular functions: To TFIIH and beyond

·        Bennett Van Houtena, , 

·        Jochen Kuperb, , 

·        Caroline Kiskerb, , 

Abstract

XPD, as part of the TFIIH complex, has classically been linked to the damage verification step of nucleotide excision repair (NER). However, recent data indicate that XPD, due to its iron-sulfur center interacts with the iron sulfur cluster assembly proteins, and may interact with other proteins in the cell to mediate a diverse set of biological functions including cell cycle regulation, mitosis, and mitochondrial function. In this perspective, after first reviewing the function and some of the key disease causing variants that affect XPD’s interaction with TFIIH and the CDK-activating kinase complex (CAK), we investigate these intriguing cellular roles of XPD and highlight important unanswered questions that provide a fertile ground for further scientific exploration.

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http://www.sciencedirect.com/science/article/pii/

S0960896615301620   

The epidemiology of neuromuscular disorders: Age at onset and gender in the Netherlands

·        Johanna C.W. Deenena

·        Pieter A. van Doornb

·        Catharina G. Faberc

·        Anneke J. van der Kooid

·        Jan B.M. Kukse

·        Nicolette C. Notermansf

·        Leo H. Visserg

·        Corinne G.C. Horlingsa

·        Jan J.G.M. Verschuurenh

·        André L.M. Verbeeki1

·        Baziel G.M. van Engelena1, , 

Abstract

Based on approximately eight years of data collection with the nationwide Computer Registry of All Myopathies and Polyneuropathies (CRAMP) in the Netherlands, recent epidemiologic information for thirty neuromuscular disorders is presented. This overview includes age and gender data for a number of neuromuscular disorders that are either relatively frequently seen in the neuromuscular clinic, or have a particular phenotype. Since 2004, over 20,000 individuals with a neuromuscular disorder were registered in CRAMP; 56% men and 44% women. The number per diagnosis varied from nine persons with Emery–Dreifuss muscular dystrophy to 2057 persons with amyotrophic lateral sclerosis. Proportions of men ranged from 38% with post-polio syndrome to 68% with progressive spinal muscular atrophy, excluding X-chromosome linked disorders. Inclusion body myositis showed the highest median age at diagnosis of 70 years. These data may be helpful in the diagnostic process in clinical practice and trial readiness.

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http://embomolmed.embopress.org/content/8/4/311

Mitochondrial disorders in children: toward development of smallmolecule treatment strategies

Werner JH Koopman, Julien Beyrath, CheukWing Fung, 

Saskia Koene,

Richard JRodenburg, Peter HGM Willems, Jan AM Smeitink

 

Abstract

This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNAencoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of wholeexome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patientderived fibroblasts, and how this information can be used for the rational design of smallmolecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease.

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http://europepmc.org/abstract/MED/27171570?source=rss 

The Effect of Piracetam on Friedreich Ataxia.

 

Elmal AD , Gündüz A , Uzun N , Apaydn H , Kzltan G

Cerrahpasa Medical Faculty Neurology Department Istanbul University Istanbul, Turkey denizelmali@yahoo.com Cerrahpasa Medical Faculty Neurology Department Istanbul University Istanbul, Turkey.

Clinical Neuropharmacology [2016, 39(3):159-160

 

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http://www.nature.com/ejhg/journal/v24/n6/full/

ejhg2015271a.html?WT.ec_id=EJHG-201606&spMailingID=51358105&spUserID=

NDQwOTM2MDQ1OQS2&spJobID

=921477021&spReportId=OTIxNDc3MDIxS0

Responsible implementation of expanded carrier screening

Lidewij Henneman1, Pascal Borry2, Davit Chokoshvili2,3, Martina C Cornel1, Carla G van El1, Francesca Forzano4, Alison Hall5, Heidi C Howard6, Sandra Janssens3, Hülya Kayserili7, Phillis Lakeman8, Anneke Lucassen9, Sylvia A Metcalfe10, Lovro Vidmar11, Guido de Wert12, Wybo J Dondorp12 and Borut Peterlin11 on behalf of the European Society of Human Genetics (ESHG)

1.   1Department of Clinical Genetics, Section Community Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands

2.   2Centre for Biomedical Ethics and Law, University of Leuven, Leuven, Belgium

3.   3Centre for Medical Genetics Ghent, University Hospital Ghent, Ghent, Belgium

4.   4Medical Genetics Unit, Ospedali Galliera, Genova, Italy

5.   5PHG Foundation, Cambridge, UK

6.   6Centre for Research Ethics and Bioethics, Uppsala University, Uppsala, Sweden

7.   7Department of Medical Genetics, Koç University School of Medicine (KUSoM), Istanbul, Turkey

8.   8Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

9.   9Department of Clinical Ethics and Law (CELS), University of Southampton and Wessex Clinical Genetic Service, Southampton, UK

10.               10Murdoch Children's Research Institute and Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia

11.               11Clinical Institute of Medical Genetics, Ljubljana University Medical Centre, Ljubljana, Slovenia

12.               12Department of Health, Ethics & Society, Research Schools CAPHRI and GROW, Maastricht University, Maastricht, The Netherlands

Abstract

This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners’ personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.

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http://www.thelancet.com/pdfs/journals/laneur/

PIIS1474-4422%2816%2900132-0.pdf
Advances in management of movement disorders in children

Anne Koy, MD correspondence email

,

 Jean-Pierre Lin, MD

,

 Terence D Sanger, MD

,

 Warren A Marks, MD

,

 Prof Jonathan W Mink, MD

,

 ProfLars Timmermann, MD

Summary

Movement disorders in children are causally and clinically heterogeneous and present in a challenging developmental context. Treatment options are broad ranging, from pharmacotherapy to invasive neuromodulation and experimental gene and stem cell therapies. The clinical effects of these therapies are variable and often poorly sustained, and only a few of the management strategies used in paediatric populations have been tested in randomised controlled studies with age-appropriate cohorts. Identification of the most appropriate treatment is uniquely challenging in children because of the incomplete knowledge about the pathophysiology of movement disorders and their influence on normal motor development; thus, effective therapeutic options for these children remain an unmet need. It is vital to transfer the expanding knowledge of the movement disorders into the development of novel symptomatic or, ideally, disease-modifying treatments, and to assess these therapeutic strategies in appropriately designed and well done trials.

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http://www.neuroanatomy.ca/flex_labs/lab8.html?id=1

IMÁGENES ANATÓMICAS EN 3D

 

 

http://www.sciencedirect.com/science/article/pii/

S0946672X16300475

Iron chelation in the treatment of neurodegenerative diseases

·        Petr Dusekab, , 

·        Susanne A. Schneiderc

·        Jan Aasethde

Abstract

Disturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson’s disease.

 

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http://www.sciencedirect.com/science/article/pii/

S0946672X16300475

Iron chelation in the treatment of neurodegenerative diseases

·        Petr Dusekab, , 

·        Susanne A. Schneiderc

·        Jan Aasethde

Abstract

Disturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson’s disease.

 

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http://www.sciencedirect.com/science/article/pii/

S0735109716010263

Translation of Human-Induced Pluripotent Stem Cells : From Clinical Trial in a Dish to Precision Medicine

·        Nazish SayedMD, PhDabc, , 

·        Chun LiuPhDabc

·        Joseph C. WuMD, PhDabc, , 

Abstract

The prospect of changing the plasticity of terminally differentiated cells toward pluripotency has completely altered the outlook for biomedical research. Human-induced pluripotent stem cells (iPSCs) provide a new source of therapeutic cells free from the ethical issues or immune barriers of human embryonic stem cells. iPSCs also confer considerable advantages over conventional methods of studying human diseases. Since its advent, iPSC technology has expanded with 3 major applications: disease modeling, regenerative therapy, and drug discovery. Here we discuss, in a comprehensive manner, the recent advances in iPSC technology in relation to basic, clinical, and population health.

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http://linkinghub.elsevier.com/retrieve/pii/

S0735109716008457?via=sd&cc=y

Constrictive Pericarditis Versus Restrictive Cardiomyopathy?
Journal of the American College of Cardiology, Volume 67, Issue 17, Pages 2061-2076
Mario J. Garcia

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http://ir.horizon-pharma.com/releasedetail.cfm?ReleaseID=969409

  Horizon Pharma plc Completes Target Enrollment of 90 Patients for Phase 3 Trial of ACTIMMUNE(R) (interferon gamma-1b) for the Treatment of People With Friedreich's Ataxia

DUBLIN, IRELAND -- (Marketwired) -- 05/05/16 -- Horizon Pharma plc (NASDAQ: HZNP), a biopharmaceutical company focused on improving patients' lives by identifying, developing, acquiring and commercializing differentiated and accessible medicines that address unmet medical needs, today announced that it has completed target enrollment of its Phase 3 study evaluating ACTIMMUNE (interferon gamma-1b) for the treatment of people with Friedreich's ataxia (FA), a degenerative neuro-muscular disorder. The study (NCT02415127) has reached its target enrollment of 90 patients at four sites in the United States, and top-line results are expected by the end of 2016.

"The achievement of this important milestone would not have been possible without the passionate commitment of people living with FA, the Friedreich's Ataxia Research Alliance and our Phase 3 study investigators," said Jeffrey W. Sherman, M.D., FACP, executive vice president, research and development and chief medical officer, Horizon Pharma plc. "We are grateful for their collective partnership and guidance, which drives our efforts toward providing a potential treatment option for this debilitating disorder."

The Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich's Ataxia study ("STEADFAST") is a randomized, multi-center, double-blind, placebo-controlled study with patients randomized 1:1 to receive subcutaneous doses of either ACTIMMUNE or placebo three times a week for a total of 26 weeks. The primary endpoint will evaluate the effect of ACTIMMUNE versus placebo on the change from baseline to Week 26 in neurological outcome as measured by a modified version of the Friedreich's Ataxia Rating Scale (FARS). The FARS is used to measure neurological signs associated with FA, with higher scores reflecting a greater level of disability. In addition to safety and efficacy, the STEADFAST trial will evaluate the pharmacokinetic characteristics of ACTIMMUNE in people with FA. After completion of the study, patients who participated in STEADFAST will have the opportunity to transition to an open-label extension study (NCT02593773).

"The prompt recruitment and enrollment of this study reflects the urgent unmet need as well as the commitment to participate in research among people living with FA," said Ronald J. Bartek, co-founder and founding president, Friedreich's Ataxia Research Alliance (FARA). "As an organization dedicated to the pursuit of scientific research leading to treatments for FA, we are very pleased with the progress of the STEADFAST study and are hopeful that the results lead to the first approved treatment for people living with FA."

In April 2015, ACTIMMUNE was granted Fast Track status for FA by the U.S. Food and Drug Administration (FDA). This designation provides greater access to and more frequent communication with the FDA throughout the entire drug development and review process, with the goal of possibly expediting approval. Fast Track designation also gives Horizon Pharma the opportunity to potentially submit sections of the ACTIMMUNE registration dossier for FA on a rolling basis, and allows ACTIMMUNE to be considered for priority review at the time of submission based on forthcoming clinical data.

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http://sciencebusiness.technewslit.com/?p=28870

Patent Granted for RNA Transcription Technology

BY ALAN, ON MAY 3RD, 2016

Jeannie Lee

Jeannie Lee (RaNA Therapeutics)

3 May 2016. A technology that blocks RNA molecules from activating chemicals in the body suppressing the working of genes to treat or prevent disease received a U.S. patent. The Patent and Trademark Office awarded patent number 9,328,346 to five inventors and assigned the patent to the parent company of Massachusetts General Hospital in Boston. The technology was licensed to RaNA Therapeutics in Cambridge, Massachusetts, co-founded by lead inventor Jeannie Lee, a professor of genetics and pathology at Mass. General and Harvard Medical School.

Lee and colleagues study regulation of long non-coding RNA in epigenetics, influences on genetic activity occurring outside the genome. RaNA Therapeutics develops therapies from oligonucleotides, small pieces of nucleic acids that in the company’s technology target specific regions of ribonucleic acid, or RNA that carries instructions from DNA in an individual’s genes to cells in the body.

RaNA Therapeutics aims its oligonucleotides at long non-coding RNA molecules attracting proteins that can modify chromatin in cells. Chromatin forms chromosomes in cells with a nucleus. This interaction of long non-coding RNA and chromatin modifiers, says the company, can suppress the normal expression of genes, thus stopping this interaction activates the gene’s expression and transcription.

The patent covers the targeting of long non-coding RNAs, as well as other nucleic acids that regulate gene expression, and methods for their use. In this case, long coding RNAs bind to chromatin modifiers in the polycomb repressive complex 2 family of proteins. These proteins are associated with the creation and maintenance of repressive chromatin environments.

RaNA Therapeutics says its technology can be applied to a variety of diseases, with the initial focus on disorders where genes’ expression of proteins in higher than normal levels is beneficial. The first therapies under development are treatments for the rare central nervous system disorders spinal muscular atrophy, caused by a loss of motor neurons in the spinal cord and brain, and Friedreich’s ataxia, an inherited disease causing damage to the nervous system and movement problems. Both programs are still in preclinical stages.

Inventor Jeannie Lee’s work with long non-coding RNA in epigenetics was recognized in her receiving this year’s Lurie Prize in biomedical sciences. The prize of $100,000 is awarded for outstanding achievement by a promising young scientist in biomedical research, by the Foundation for the National Institutes of Health. The award was announced in mid-February.

Read more:

 

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http://actaneurocomms.biomedcentral.com/articles/

10.1186/s40478-016-0288-5 
Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation

·        Arnulf H. Koeppen

·        R. Liane Ramirez,

·        Alyssa B. Becker and

·        Joseph E. Mazurkiewicz

Abstract

Introduction

Dorsal root ganglia (DRG) are highly vulnerable to frataxin deficiency in Friedreich ataxia (FA), an autosomal recessive disease due to pathogenic homozygous guanine-adenine-adenine trinucleotide repeat expansions in intron 1 of the FXN gene (chromosome 9q21.11). An immunohistochemical and immunofluorescence study of DRG in 15 FA cases and 12 controls revealed that FA causes major primary changes in satellite cells and inflammatory destruction of neurons. A panel of antibodies was used to reveal the cytoplasm of satellite cells (glutamine synthetase, S100, metabotropic glutamate receptors 2/3, excitatory amino acid transporter 1, ATP-sensitive inward rectifier potassium channel 10, and cytosolic ferritin), gap junctions (connexin 43), basement membranes (laminin), mitochondria (ATP synthase subunit beta and frataxin), and monocytes (CD68 and IBA1).

Results

Reaction product of the cytoplasmic markers and laminin confirmed proliferation of satellite cells and processes into multiple perineuronal layers and residual nodules. The formation of connexin 43-reactive gap junctions between satellite cells was strongly upregulated. Proliferating satellite cells in FA displayed many more frataxin- and ATP5B-reactive mitochondria than normal. Monocytes entered into the satellite cell layer, appeared to penetrate neuronal plasma membranes, and infiltrated residual nodules. Satellite cells and IBA1-reactive monocytes displayed upregulated ferritin biosynthesis, which was most likely due to leakage of iron from dying neurons.

Conclusions

We conclude that FA differentially affects the key cellular elements of DRG, and postulate that the disease causes loss of bidirectional trophic support between satellite cells and neurons.

 

 

 

 

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