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Heterologous mitochondrial targeting sequences can deliver functional proteins into mitochondria

·        Dana Marcusa1

·        Michal Lichtensteina1

·        Natali Cohena

·        Rita Hadada

·        Tal Erlich-Hadada

·        Hagar Greifb,

·        Haya Lorberboum-Galskia, , 



Mitochondrial Targeting Sequences (MTSs) are responsible for trafficking nuclear-encoded proteins into mitochondria. Once entering the mitochondria, the MTS is recognized and cleaved off. Some MTSs are long and undergo two-step processing, as in the case of the human frataxin (FXN) protein (80aa), implicated in Friedreich's ataxia (FA). Therefore, we chose the FXN protein to examine whether nuclear-encoded mitochondrial proteins can efficiently be targeted via a heterologous MTS (hMTS) and deliver a functional protein into mitochondria.

We examined three hMTSs; that of citrate synthase (cs), lipoamide deydrogenase (LAD) and C6ORF66 (ORF), as classically MTS sequences, known to be removed by one-step processing, to deliver FXN into mitochondria, in the form of fusion proteins. We demonstrate that using hMTSs for delivering FXN results in the production of 4–5-fold larger amounts of the fusion proteins, and at 4–5-fold higher concentrations. Moreover, hMTSs delivered a functional FXN protein into the mitochondria even more efficiently than the native MTSfxn, as evidenced by the rescue of FA patients’ cells from oxidative stress; demonstrating a 18%–54% increase in cell survival; and a 13%-33% increase in ATP levels, as compared to the fusion protein carrying the native MTS. One fusion protein with MTScs increased aconitase activity within patients’ cells, by 400-fold.

The implications form our studies are of vast importance for both basic and translational research of mitochondrial proteins as any mitochondrial protein can be delivered efficiently by an hMTS. Moreover, effective targeting of functional proteins is important for restoration of mitochondrial function and treatment of related disorders.




Cellular thiamine status is coupled to function of mitochondrial 2-oxoglutarate dehydrogenase

·        G. Mkrtchyana

·        A. Grafbc

·        L. Bettendorffd

·        V. Bunikae, , 



Decreased thiamine and reduced activity of thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase (OGDH) cause neurodegeneration. We hypothesized on concerted cell-specific regulation of the thiamine metabolism and ThDP-dependent reactions. We identified a smaller thiamine pool, a lower expression of the mitochondrial ThDP transporter, and a higher expression of OGDH in rat astrocytes versusneuroblastoma N2A. According to the data, the astrocytic OGDH may be up-regulated by an increase in intracellular ThDP, while the neuroblastomal OGDH functions at full ThDP saturation. Indeed, in rat astrocytes and brain cortex, OGDH inhibition by succinyl phosphonate (SP) enlarged the pool of thiamine compounds. Increased ThDP level in response to the OGDH inhibition presumably up-regulated the enzyme to compensate for a decrease in reducing power which occurred in SP-treated astrocytes. Under the same SP treatment of N2A cells, their thiamine pool and reducing power were unchanged, although SP action was evident from accumulation of glutamate. The presented data indicate that functional interplay between OGDH, other proteins of the tricarbocylic acid cycle and proteins of thiamine metabolism is an important determinant of physiology-specific networks and their homeostatic mechanisms.



Iron related hemochromatosis (HFE) gene mutations in Friedreich Ataxia patients

Inder Singh1

Sunil Shakya1

Rakesh Kumar Singh

Istaq Ahmad

Vinay Goyal

Garima Shukla

Madakasira Vasantha Padma Srivastava

Neuroscience Centre, All India Institute of Medical Sciences, New Delhi-110029, India

Mohammed Faruq Press enter key for correspondence

information Press enter key to Email the author

CSIR-Institutes of Genomics and Integrative Biology, New Delhi-110007, India

Achal Kumar Srivastava Press enter key for correspondence information Press enter key to Email the author

Neuroscience Centre, All India Institute of Medical Sciences, New Delhi 110029, India

The role of oxidative stress and dysregulation of iron metabolism in the pathogenesis of Friedreich's Ataxia (FRDA) has been observed in several FRDA patients and models [1]. The HFE gene on chromosome 6 is a corpuscular hemoglobin class I–like molecule related to iron regulation. Mutations in HFE results in hereditary hemochromatosis (HH), a condition of iron overload disorder [2]. Clinical and demographic heterogeneity in FRDA across different populations are attributed to various genetic causes.



Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

To cite this article: Polak Urszula, Li Yanjie, Butler Jill Sergesketter, and Napierala Marek. Stem Cells and Development. October 2016, ahead of print.

Author information

Urszula Polak,1 Yanjie Li,2 Jill Sergesketter Butler,2 and Marek Napierala2,3

1Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Smithville, Texas.

2Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama.

3Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.

Address correspondence to:

Dr. Marek Napierala

Department of Biochemistry and Molecular Genetics

UAB Stem Cell Institute

University of Alabama at Birmingham

1825 University Boulevard

Birmingham, AL 35294


Dr. Jill Sergesketter Butler

Department of Biochemistry and Molecular Genetics

UAB Stem Cell Institute

University of Alabama at Birmingham

1825 University Boulevard

Birmingham, AL 35294



Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. This severe neurodegenerative disease is caused by an expansion of guanine-adenine-adenine (GAA) repeats located in the first intron of the frataxin (FXN) gene, which represses its transcription. Although transcriptional silencing is associated with heterochromatin-like changes in the vicinity of the expanded GAAs, the exact mechanism and pathways involved in transcriptional inhibition are largely unknown. As major remodeling of the epigenome is associated with somatic cell reprogramming, modulating chromatin modification pathways during the cellular transition from a somatic to a pluripotent state is likely to generate permanent changes to the epigenetic landscape. We hypothesize that the epigenetic modifications in the vicinity of the GAA repeats can be reversed by pharmacological modulation during somatic cell reprogramming. We reprogrammed FRDA fibroblasts into induced pluripotent stem cells (iPSCs) in the presence of various small molecules that target DNA methylation and histone acetylation and methylation. Treatment of FRDA iPSCs with two compounds, sodium butyrate (NaB) and Parnate, led to an increase in FXNexpression and correction of repressive marks at the FXN locus, which persisted for several passages. However, prolonged culture of the epigenetically modified FRDA iPSCs led to progressive expansions of the GAA repeats and a corresponding decrease in FXN expression. Furthermore, we uncovered that differentiation of these iPSCs into neurons also results in resilencing of the FXN gene. Taken together, these results demonstrate that transcriptional repression caused by long GAA repeat tracts can be partially or transiently reversed by altering particular epigenetic modifications, thus revealing possibilities for detailed analyses of silencing mechanism and development of new therapeutic approaches for FRDA.




Dr. Archana Mogili1 Dr. Mrudula Sankaramanchi2 Dr. C H.Sadanandam3 1,2PG Scholar, 3Guide Dr. B.R.K.R.Govt.Ayurvedic College, Hyderabad, Telangana, India



Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds

·        Ana Paula Terrassoab

·        Ana Carina Silvaab

·        Augusto Filipec

·        Pedro Pedrosoc

·        Ana Lúcia Ferreirac

·        Paula Marques Alvesab

·        Catarina Britoab, , 



Central nervous system drug development has registered high attrition rates, mainly due to the lack of efficacy of drug candidates, highlighting the low reliability of the models used in early-stage drug development and the need for new in vitro human cell-based models and assays to accurately identify and validate drug candidates. 3D human cell models can include different tissue cell types and represent the spatiotemporal context of the original tissue (co-cultures), allowing the establishment of biologically-relevant cell-cell and cell-extracellular matrix interactions. Nevertheless, exploitation of these 3D models for neuroprotection assessment has been limited due to the lack of data to validate such 3D co-culture approaches.


In this work we combined a 3D human neuron-astrocyte co-culture with a cell viability endpoint for the implementation of a novel in vitro neuroprotection assay, over an oxidative insult. Neuroprotection assay robustness and specificity, and the applicability of Presto Blue, MTT and CytoTox-Glo viability assays to the 3D co-culture were evaluated.


Presto Blue was the adequate endpoint as it is non-destructive and is a simpler and reliable assay. Semi-automation of the cell viability endpoint was performed, indicating that the assay setup is amenable to be transferred to automated screening platforms. Finally, the neuroprotection assay setup was applied to a series of 36 test compounds and several candidates with higher neuroprotective effect than the positive control, Idebenone, were identified.


The robustness and simplicity of the implemented neuroprotection assay with the cell viability endpoint enables the use of more complex and reliable 3D in vitro cell models to identify and validate drug candidates.


·        3D co-culture; 

·        Astrocyte; 

·        Human neurotoxicity; 

·        In vitro assay; 

·        Neuron; 

·        Neuroprotection



Applications of CRISPR/Cas9 for Gene Editing in Hereditary Movement Disorders

Wooseok Im1, Jangsup Moon1, Manho Kim1, 2

1Department of Neurology, Neuroscience Research Center, Seoul National University Hospital, Seoul, Korea

2Protein Metabolism Medical Research Center, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Manho Kim, MD, PhD, Department of Neurology, Neuroscience Research Center, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-2193 Fax: +82-2-3672-7553


* These authors contributed equally to this work.


Gene therapy is a potential therapeutic strategy for treating hereditary movement disorders, including hereditary ataxia, dystonia, Huntington’s disease, and Parkinson’s disease. Genome editing is a type of genetic engineering in which DNA is inserted, deleted or replaced in the genome using modified nucleases. Recently, clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 (CRISPR/Cas9) has been used as an essential tool in biotechnology. Cas9 is an RNA-guided DNA endonuclease enzyme that was originally associated with the adaptive immune system of Streptococcus pyogenes and is now being utilized as a genome editing tool to induce double strand breaks in DNA. CRISPR/Cas9 has advantages in terms of clinical applicability over other genome editing technologies such as zinc-finger nucleases and transcription activator-like effector nucleases because of easy in vivodelivery. Here, we review and discuss the applicability of CRISPR/Cas9 to preclinical studies or gene therapy in hereditary movement disorders.

Key Words: CRISPR/Cas9gene editinggene therapy;

 hereditary movement disorders




hiPSC Disease Modeling of Rare Hereditary Cerebellar Ataxias

Opportunities and Future Challenges

1.  Dunja Lukovic1,2

2.  Victoria Moreno-Manzano3

3.  Francisco Javier Rodriguez-Jimenez1

4.  Angel Vilches1

5.  Eva Sykova4

6.  Pavla Jendelova4

7.  Miodrag Stojkovic5,6

8.  Slaven Erceg1,2,4

1.   1Stem Cells Therapies in Neurodegenerative Diseases Lab, Research Center “Principe Felipe,” Valencia, Spain

2.   2National Stem Cell Bank-Valencia Node, Biomolecular and Bioinformatics Resources Platform PRB2, ISCIII, Research Center “Principe Felipe,” Valencia, Spain

3.   3Neuronal and Tissue Regeneration Lab, Research Center “Principe Felipe,” Valencia, Spain

4.   4Institute of Experimental Medicine, Department of Neuroscience, Academy of Science of the Czech Republic, Prague, Czech Republic

5.   5Spebo Medical, Leskovac, Serbia

6.   6Human Genetics Department, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

1.   Slaven Erceg, Stem Cells Therapies in Neurodegenerative Diseases Lab, Research Center “Principe Felipe,” C/ Eduardo Primo Yúfera 3, Valencia 46012, Spain.


Cerebellar ataxias are clinically and genetically heterogeneous diseases affecting primary cerebellar cells. The lack of availability of affected tissue from cerebellar ataxias patients is the main obstacle in investigating the pathogenicity of these diseases. The landmark discovery of human-induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells with an unlimited self-renewing capacity. Additionally, their potential to differentiate into virtually any cell type of the human organism allows for large amounts of affected cells to be generated in culture, converting this hiPSC technology into a revolutionary tool in the study of the mechanisms of disease, drug discovery, and gene correction. In this review, we will summarize the current studies in which hiPSC were utilized to study cerebellar ataxias. Describing the currently available 2D and 3D hiPSC-based cellular models, and due to the fact that extracerebellar cells were used to model these diseases, we will discuss whether or not they represent a faithful cellular model and whether they have contributed to a better understanding of disease mechanisms.



New Reasons to Pursue the Therapeutic Potential of Synthetic Nucleic Acids for Neurological Diseases

Jill Sergesketter Butler, PhD1Marek Napierala, PhD1,2

The use of short, synthetic nucleic acids as potential therapeutics was proposed more than 3 decades ago. However, improvements in the design and synthesis of nucleic acids have recently piqued the interest of researchers and physicians searching for alternative approaches for treating diseases that do not conform to traditional drug discovery programs. The advent of novel modified nucleic acids with better efficacy, stability, and cell penetrance combined with advancements in various delivery systems and methods, including intrathecal administration to allow direct entry to the central nervous system, provide sufficient rationale to cultivate the therapeutic capabilities of synthetic nucleic acids for neurological diseases.


------------------------------------------------------------------------------ Synthetic Nucleic Acids and Treatment of Neurological Diseases

David R. Corey, PhD1,2

Key Points

Question  What is the status of using oligonucleotides to modulate gene expression for the treatment of neurological diseases?

Findings  Work using oligonucleotides to modulate expression of frataxin and survival motor neuron proteins demonstrates progress in both the basic and clinical science.

Meaning  The significance of oligonucleotides as a treatment strategy for neurological diseases is likely to increase.


Importance  The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease.

Objective  To review the use of ASOs for the treatment of neurological disorders.

Evidence Review  Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich’s ataxia) and production of active survival motor neuron 2 (SMN2, spinal muscular atrophy).

Findings  Many neurological diseases are caused by inappropriate expression of a protein. Mutations may reduce expression of a wild-type protein, and strategies to activate expression may provide therapeutic benefit. For other diseases, a mutant protein may be expressed too highly and methods that reduce mutant protein expression might form the basis for drug development. Synthetic ASOs can recognize cellular RNA and control gene expression. Antisense oligonucleotides are not a new concept, but successful clinical development has proceeded at a slow pace. Advances in ASO chemistry, biological understanding, and clinical design are making successful applications more likely.

Conclusions and Relevance  Both laboratory and clinical studies are demonstrating the potential of ASOs as a source of drugs to treat neurological disease.




Modeling and correction of structural variations in patient-derived iPSCs using CRISPR/Cas9

·        Chul-Yong Park,

·        Jin Jea Sung,

·        Sang-Hwi Choi,

·        Dongjin R Lee,

·        In-Hyun Park

·        & Dong-Wook Kim



Genome engineering technology using engineered nucleases has been rapidly developing, enabling the efficient correction of simple mutations. However, the precise correction of structural variations (SVs) such as large inversions remains limited. Here we describe a detailed procedure for the modeling or correction of large chromosomal rearrangements and short nucleotide repeat expansions using engineered nucleases in human induced pluripotent stem cells (hiPSCs) from a healthy donor and patients with SVs. This protocol includes the delivery of engineered nucleases with no donor template to hiPSCs, and genotyping and derivation/characterization of gene-manipulated hiPSC clones. With engineered nucleases, genomic inversions, reversions, and deletions of short nucleotide expansions can be identified in 2 weeks, and desired clones can be generated in as little as 3–4 weeks. This protocol enables the correction of large inverted segments and short nucleotide repeat expansions in diseases such as hemophilia A, fragile X syndrome, Hunter syndrome, and Friedreich's ataxia.




NRF2 in neurodegenerative diseases

·        Antonio Cuadrado



Neurodegenerative diseases, and degenerative disorders as a whole, share in common the deviation from homeostatic responses related to the control of proteostasis and low-grade chronic oxidative, inflammatory, and metabolic stress. These are all crucial events where transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a very important defensive role. In this paper, biochemical and genetic evidence connecting NRF2 with neurodegenerative diseases will be discussed, mainly in the context of preclinical mouse models and in patients with Alzheimer's and Parkinson's disease. NRF2 can be targeted pharmacologically and the most successful drugs to endorse a neuroprotective therapy will be commented, including dimethyl fumarate.



A neurodegenerative perspective on mitochondrial optic neuropathies

·        Patrick Yu-Wai-Man 

·        , Marcela Votruba

·        , Florence Burté

·        , Chiara La Morgia

·        , Piero Barboni

·        ,Valerio Carelli


Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.




Dr. Jacques P. Tremblay from University of Laval, Quebec joins the speaker panel for the 2nd Annual Genome Editing & Engineering Conference


 MarketsandMarkets Conferences are excited to introduce the 2nd Annual Genome Editing & Engineering Conference (6th - 7th February 2017 in San Diego).The conference brings together the key industry leaders and researchers to address the concepts, challenges & applications of the genome editing tools like CRISPR/Cas9, TALENs. 

·      (1888PressRelease) October 01, 2016 - MarketsandMarkets Conferences, who are organizing the 2nd Annual Genome Editing & Engineering Conference, confirmed today that Dr. Jacques P. Tremblay, Full Professor, Department of Molecular Medicine, University of Laval, Quebec, Canada has joined the speaker panel for the conference. The event co - located with the 2nd Annual Biomarker Conference and 2nd annual NGS Data Analysis and Informatics Conference is scheduled for 6th - 7th February 2017 in San Diego, CA. The conference will gather key industry leaders and researchers from academia, pharma and bio - pharma organizations to address the concepts, challenges and applications of genome editing tools like CRISPR/Cas9, TALENs. The marketing team at MarketsandMarkets Conferences did a small pre - event interview with Dr. Tremblay, talking about emerging research areas in genome editing and engineering. Dr. Tremblay said, "Cancer is due to multiple genetic and epigenetic alterations that drive abnormal cell proliferation and permit resistance to chemotherapy. CRISPR/Cas9 permits to correct or ablate such mutations and thus may eventually permit to treat cancer". He further added, "Because of its high efficiency and accuracy, CRISPR/Cas9 genome editing technique is already used to explore in cancer therapies. Several studies used CRISPR/Cas9 to target cancer cell mutations in cellular and animal cancer models. This may permit to demonstrate their therapeutic potential. CRISPR/Cas9 may also be used to fight oncogenic infections, explore anticancer drugs, and engineer immune cells and oncolytic viruses for immunotherapy of cancer. However, there is still a lot of research to be done before the first clinical application. Dr. Tremblay will be presenting at the conference on use of CRISPR/Cas9 system to correct mutations responsible for Duchenne Muscular Dystrophy and Friedreich ataxia. Joining Dr. Tremblay on the panel will be experts representing organizations such as University of Utah School of Medicine, Massachusetts Institute of Technology, J. Craig Venter Institute, University of Nebraska Medical Center, University of California, University of Washington, University of Southern California, University of Rochester, National Institutes of Health, University of Texas, University of Minnesota, Hiroshima University and Wellcome Trust Sanger Institute. Special emphasis will be given on CRISPR system - addressing the concept, technology and challenges like integration of genome, off-target effects, and delivery systems. Taking these elements into consideration some of the key topics of discussion at the conference will be RNA guided nuclease for genome modifications, different gene delivery systems, CRISPR as a molecular tool for programmable gene expression and gene therapy, human gene therapy using Zebrafish model, gene knock in and genomic screening using TALEN and CRISPR, CRISPR biomedical research applications, RNAi based screening technologies, genome editing for disease modeling and NgAgo as the latest tool for genome editing. The conference will be an excellent opportunity to network, share expertise with industry peers and stay updated about the latest advancements in genomics and gene engineering. The conference is supported by California Life Sciences Association (CLSA), ArizonaBio, BioUtah, Colorado BioScience Association, Georgia Bio, Northwest Association for Biomedical Research (NWABR) and The Bioscience Association of Maine (BAM).



Late-Onset Friedreich’s Ataxia (LOFA) Mimicking Charcot–Marie–Tooth Disease Type 2: What Is Similar and What Is Different?

·        Rubens Paulo A. Salomão

·        , Maria Thereza Drumond Gama

·        , Flávio Moura Rezende Filho

·        ,Fernanda Maggi

·        , José Luiz Pedroso 

·        , Orlando G. P. Barsottini



Herein, we report a patient that presented with late-onset progressive steppage gait, neuropathy andpes cavus, suggesting Charcot–Marie–Tooth (CMT) disease. Subsequent genetic investigation confirmed Friedreich’s ataxia (FRDA). We demonstrate that late-onset Friedreich’s ataxia (LOFA) may be a CMT mimicker. This case reinforces that other genetic conditions may clinically resemble CMT. The clinical similarities between CMT and FRDA include a symmetrical neuropathy (axonal in FRDA), steppage gait, and eventually scoliosis. We suggest that late-onset forms of hereditary neuropathies should be carefully evaluated, since LOFA may be a CMT mimicker.


Hereditary ataxias hereditary neuropathies Charcot–Marie–Tooth disease Friedreich’s ataxia

Electronic supplementary material

The online version of this article

(doi:10.​1007/​s12311-016-0822-9) contains supplementary material, which is available to authorized users.




Congenital and Hereditary Diseases of the Spinal Cord

·        Lily L. Wang, MBBS, MPH, , , 

·        Karin S. Bierbrauer, MD§


Congenital anomalies of the spinal cord can pose a diagnostic dilemma to the radiologist. Several classification systems of these anomalies exist. Antenatal ultrasound and fetal magnetic resonance imaging is playing an increasingly important role in the early diagnosis and management of patients. Understanding the underlying anatomy as well as embryology of these disorders can be valuable in correctly identifying the type of spinal cord dysraphic defect.

Hereditary spinal cord diseases are rare but can be devastating. When the onset is in adulthood, delay in diagnosis is common. Although the spine findings are nonspecific, some imaging features combined with brain imaging findings can be distinctive. Sometimes, the radiologist may be the first to raise the possibility of these disorders.

Address reprint requests to Lily L. Wang, MBBS, MPH, Department of Radiology, University of Cincinnati Medical Center, Cincinnati, OH.

© 2016 Elsevier Inc. All rights reserved.

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A longitudinal study of the SF-36 version 2 in Friedreich ataxia

1.   G. Tai1, 

2.   L. A. Corben1,2,3,4, 

3.   E. M. Yiu1,3,5and

4.   M. B. Delatycki1,2,3,6,




The Medical Outcomes Study 36 item Short-Form Health Survey (SF-36) is one of the most commonly used patient reported outcome measure. This study aimed to examine the relationship between SF-36 version 2 (SF-36V2) summary scores and Friedreich ataxia (FRDA) clinical characteristics, and to investigate the responsiveness of the scale, in comparison with the Friedreich Ataxia Rating Scale (FARS), over 1, 2 and 3 years.

Materials and Methods

Descriptive statistics were used to examine the characteristics of the cohort at baseline and years 1, 2 and 3. Correlations between FRDA clinical characteristics and SF-36V2 summary scores were reported. Responsiveness was measured using paired t tests.


We found significant correlations between the physical component summary (PCS) of the SF-36V2 and various FRDA clinical parameters but none for the mental component summary. No significant changes in the SF-36V2 were seen over 1 or 2 years; however, PCS scores at Year 3 were significantly lower than at baseline (−3.3, SD [7.6], P=.01). FARS scores were found to be significantly greater at Years 1, 2 and 3 when compared to baseline.


Our findings suggest that despite physical decline, individuals with FRDA have relatively stable mental well-being. This study demonstrates that the SF-36V2 is unlikely to be a useful tool for identifying clinical change in FRDA therapeutic trials.


-------------------------------------------------------- Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

Semiha Kurt,1 Betul Cevik,1 Durdane Aksoy,1 E. Irmak Sahbaz,2 Aslı Gundogdu Eken,2 and A. Nazli Basak2

1Department of Neurology, Gaziosmanpasa University Faculty of Medicine, 60100 Tokat, Turkey 2Suna and Inan Kıraç Foundation Neurodegeneration Research Laboratory, Molecular Biology and Genetics Department, Bogazici University, 34342 Istanbul, Turkey


Here, we describe the clinical features of several members of the same family diagnosed with Friedreich ataxia (FRDA) and cerebral lesions, demyelinating neuropathy, and late-age onset without a significant cardiac involvement and presenting with similar symptoms, although genetic testing was negative for the GAA repeat expansion in one patient of the family. The GAA repeat expansion in the frataxin gene was shown in all of the family members except in a young female patient. MRI revealed arachnoid cysts in two patients; MRI was consistent with both cavum septum pellucidum-cavum vergae and nodular signal intensity increase in one patient. EMG showed demyelinating sensorimotor polyneuropathy in another patient. The GAA expansion-negative 11-year-old female patient had mental-motor retardation, epilepsy, and ataxia. None of the patients had significant cardiac symptoms. Description of FRDA families with different ethnic backgrounds may assist in identifying possible phenotypic and genetic features of the disease. Furthermore, the genetic heterogeneity observed in this family draws attention to the difficulty of genetic counseling in an inbred population and to the need for genotyping all affected members before delivering comprehensive genetic counseling.



Studying the pathophysiologic connection between cardiovascular and nervous systems using stem cells

1.   Volkan Coskun* and

2.   Dawn M. Lombardo



The physiological basis of therapies for cerebellar ataxias

1.  Hiroshi Mitoma

1.   Department of Medical Education, Tokyo Medical University, 6-7-1 Nishi-shinjyuku, Shinjyuku-ku, Tokyo, 160-0023, Japan

2.  Mario Manto

1.   Unité d’Etude du Mouvement (UEM), FNRS, Neurologie ULB-Erasme, Brussels, Belgium Université de Mons, Mons, Belgium



Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of ‘restorable stage’. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools.




Emerging therapies for mitochondrial disorders

Helen Nightingale, Gerald Pfeffer, David Bargiela, 

Rita Horvath, Patrick F. Chinnery


Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a clear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough.

  Abbreviations


adeno-associated viral vector

Cas9 =

clustered regularly interspaced short palindromic repeats associated protein 9


cytochrome c oxidase


Leber hereditary optic neuropathy


mitochondrial neurogastrointestinal encephalopathy


poly ADP (adenosine diphosphate-ribose) polymerase

PGC-1α =

peroxisome proliferator-activated receptor gamma coactivator-1-alpha


peroxisome proliferator-activated receptors


transcription activator-like effectors nucleases


zinc finger nuclease




Population-based preconception carrier screening: how potential users from the general population view a test for 50 serious diseases EJHGOpen

Mirjam Plantinga1, Erwin Birnie1, Kristin M Abbott1, Richard J Sinke1, Anneke M Lucassen2, Juliette Schuurmans1, Seyma Kaplan1, Marian A Verkerk3, Adelita V Ranchor4 and Irene M van Langen1

1.   1Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

2.   2Clinical Ethics and Law, Faculty of Medicine, University of Southampton, Southampton, UK

3.   3Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

4.   4Department of Health Psychology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Correspondence: Dr M Plantinga, Department of Genetics, University Medical Center Groningen, University of Groningen, CB50, PO Box 30.001, 9700 RB Groningen, The Netherlands. Tel: +31 50 3617100; Fax: +31 50 3617230; E-mail:

Received 29 October 2015; Revised 17 February 2016; Accepted 7 April 2016 Advance online publication 11 May 2016

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With the increased international focus on personalized health care and preventive medicine, next-generation sequencing (NGS) has substantially expanded the options for carrier screening of serious, recessively inherited diseases. NGS screening tests not only offer reproductive options not previously available to couples, but they may also ultimately reduce the number of children born with devastating disorders. To date, preconception carrier screening (PCS) has largely targeted single diseases such as cystic fibrosis, but NGS allows the testing of many genes or diseases simultaneously. We have developed an expanded NGS PCS test for couples; simultaneously it covers 50 very serious, early-onset, autosomal recessive diseases that are untreatable. This is the first, noncommercial, population-based, expanded PCS test to be offered prospectively to couples in a health-care setting in Europe. So far, little is known about how potential users view such a PCS test. We therefore performed an online survey in 2014 among 500 people from the target population in the Netherlands. We enquired about their intention to take an expanded PCS test if one was offered, and through which provider they would like to see it offered. One-third of the respondents said they would take such a test were it to be offered. The majority (44%) preferred the test to be offered via their general practitioner (GP) and 58% would be willing to pay for the test, with a median cost of  75. Our next step is to perform an implementation study in which this PCS test will be provided via selected GPs in the Northern Netherlands.




You should at least ask’. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research

Pauline McCormack, Anna Kole, Sabina Gainotti, Deborah Mascalzoni, Caron Molster, Hanns Lochmüller and Simon Woods


Within the myriad articles about participants’ opinions of genomics research, the views of a distinct group – people with a rare disease (RD) – are unknown. It is important to understand if their opinions differ from the general public by dint of having a rare disease and vulnerabilities inherent in this. Here we document RD patients’ attitudes to participation in genomics research, particularly around large-scale, international data and biosample sharing. This work is unique in exploring the views of people with a range of rare disorders from many different countries. The authors work within an international, multidisciplinary consortium, RD-Connect, which has developed an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for RD research. Focus groups were conducted with 52 RD patients from 16 countries. Using a scenario-based approach, participants were encouraged to raise topics relevant to their own experiences, rather than these being determined by the researcher. Issues include wide data sharing, and consent for new uses of historic samples and for children. Focus group members are positively disposed towards research and towards allowing data and biosamples to be shared internationally. Expressions of trust and attitudes to risk are often affected by the nature of the RD which they have experience of, as well as regulatory and cultural practices in their home country. Participants are concerned about data security and misuse. There is an acute recognition of the vulnerability inherent in having a RD and the possibility that open knowledge of this could lead to discrimination.



Longitudinal study of gait lower limb coordination and rehabilitative indications in patients affected by Ataxia of Friedreich (FRDA)

M. Petrarca

G. Vasco

S. Gazzellini

S. Carniel

A. Pisano

E. Bertini

E. Castelli

Bambino Gesù Children's Hospital, Rome, Italy




Retrotope Announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich's Ataxia

First-in-Human Trial Achieves Safety, Tolerability, and PK Goals, With Early Signals of Efficacy

LOS ALTOS, CA--(Marketwired - Sep 16, 2016) - Dr. Theresa Zesiewicz, principal investigator in Retrotope's first-in-human clinical trial of RT001 in Friedreich's ataxia (FA), today presented early results from Retrotope's Phase I/II trial conducted at the University of South Florida Ataxia Research Center and the Collaborative NeuroSciences Network in Long Beach, CA. The trial, a randomized, double-blind, comparator controlled, two-dose study of RT001 in 18 FA patients for 28 days, met all of its primary safety, tolerability and pharmacokinetic (PK) goals. While biological activity was not a primary goal of the study, a number of clinically important activity measures were tested, found to be highly correlated to well-studied disease severity scales and showed multiple, unexpected, robust signals of drug effect at one or more doses.

Dr. Theresa Zesiewicz, principal investigator of the study, said, "It is impressive that multiple efficacy indications moved in the right direction in only 28 days in such a small study. This drug clearly deserves immediate further study in FA, which results in a slow, but steady decline in muscular and neurological function."

Curtis Scribner, MD, CMO of Retrotope, commented, "This study met and exceeded all of its goals. The trial creates a profile of an extremely well-behaved drug: safe, well-tolerated at high doses, and rapidly adsorbed to target levels determined in preclinical studies." 

Retrotope was also able to identify its maximum tolerated dose level (MTD) of RT001 due to one severe adverse event at the highest dose (9g/day), uncontrolled diarrhea, experienced by a subject with very low body mass index (BMI). This is a common complication of high fish oil dosing in hypercholesterolemia. Other adverse events were either very mild or not drug related. Fatty acid metabolites of RT001 were also detected in multiple blood compartments demonstrating the drug participated in normal fatty acid processing.

Retrotope is announcing an extension study in which the same patients which will re-randomize into treatment and comparator arms for 6 months. The goals of this study will be to refine dose determination under a relaxed (from the original study) low polyunsaturated fatty acid (PUFA) diet, establish longer term durability of clinical effects, and longer term safety. For more information on the current study, please visit:

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. There is currently no approved treatment for FA. Earlier this year, the FDA granted Retrotope Orphan Drug Designation for RT001 in FA.

Bob Molinari, Ph.D., CEO of Retrotope, said, "This study would not have been possible without the support and guidance provided by the Friedreich's Ataxia Research Alliance (FARA) and the clinicians in its network, particularly Dr. Rob Wilson at the University of Pennsylvania Perlman School of Medicine, Dr. Susan Perlman at UCLA, and importantly, Jen Farmer and her team at FARA. They tirelessly assisted in organizing patient recruitment, paid large parts of patients' travel costs to trial sites, and consulted with us on all aspects of trial design. This organization makes FA trials possible and successful."

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

About Retrotope Retrotope, a privately-held, clinical-stage pharmaceutical company, is creating a new category of drugs to treat degenerative diseases. Composed of proprietary compounds that are chemically stabilized forms of essential nutrients, these compounds are being studied as disease modifying therapies for many intractable diseases such as Parkinson's, Alzheimer's, mitochondrial myopathies, and retinopathies. RT001, Retrotope's first lead candidate, is for the treatment of Friedreich's ataxia, a fatal orphan disease. For more information about Retrotope, please visit

About FARA: The Friedreich's Ataxia Research Alliance (FARA) is a national, public, 501(c)(3), non-profit, tax exempt organization dedicated to curing Friedreich's ataxia (FA), a rare neuromuscular disorder, through research. For more information about FA, visit the FARA website at


·        Retrotope Media Contact Rick Roose CoActive PR 415-202-4445 SOURCE: Retrotope, Inc. 4300 El Camino Real, Suite 201 Los Altos, CA 94022 650-575-7551



UF and the Advocacy Group GoFAR Announce Gene Therapy program for Friedreich’s Ataxia


L’Università della Florida e GoFAR Annunciano un programma di Terapia Genica per l’ Atassia di Friedreich Gainesville, FL, 13 Settembre, 2016 – Ricercatori dell’Università della Florida hanno ricevuto dall’ associazione italiana dei pazienti GoFAR un finanziamento per lo sviluppo di un programma di terapia genica rivolto a trattare l’ Atassia di Friedreich, un progressivo e debilitante disordine neuromuscolare. GoFAR ha conferito il finanziamento di circa 750.000 $ a Manuela Corti, PT, PhD del Powell Gene Therapy Center dell’Università della Florida per lo svolgimento di un programma completo di terapia genica della durata di 18 mesi, rivolto a correggere il difetto di base che determina l’atassia di Friedreich (AF). Il programma includerà sia gli studi preclinici sia la pianificazione degli studi clinici sugli umani. La AF è una malattia genetica causata dal funzionamento difettoso del gene della fratassina. I sintomi della AF usualmente compaiono nella tarda infanzia e includono la progressiva perdita delle funzioni neuro-muscolari e della coordinazione fisica. La AF colpisce circa 1 persona ogni 50.000 e può anche causare problemi cardiaci, diabete e morte prematura. Questo progetto di terapia genica mira a trattare contemporaneamente sia l’aspetto cardiologico sia quello neurologico della patologia, mediante l’inserimento nel cuore e nel sistema nervoso di un gene della fratassina funzionante, utilizzando come vettore un virus adeno-associato.Per raggiungere gli obiettivi preposti, il progetto impiegherà diverse nuove procedure. La dottoressa Corti, insieme al Direttore del Gene Therapy Center, Dottor Barry Byrne, MD, PhD, inizierà il programma questo mese. “Il progetto rappresenta una importante pietra miliare nello sviluppo di una strategia di cura che potrebbe migliorare drasticamente la qualità di vita dei pazienti” ha affermato Manuela Corti. Filomena D’Agostino, Presidente del Comitato RUDI ONLUS, conosciuto anche come GoFAR, ha dichiarato, “GoFAR è felice di attribuire questo finanziamento alla Dott.ssa Corti e al Dottor Byrne per quello che si connota essere il primo programma completo di terapia genica per la AF. GoFAR garantirà supporto continuativo a questo team e ad altri impegnati ad avanzare negli studi clinici sulle persone i trattamenti di terapia genica per la AF. Noi ci auguriamo che la innovativa strategia adottata da GoFAR nel supportare finanziariamente una istituzione pubblica con esperienza significativa nei trattamenti di terapia genica per le malattie rare, aumenti notevolmente l’ opportunità per i pazienti di partecipare allo sviluppo di un trattamento efficace” “Al Clinical and Translational Science Institute (CTSI) dell’Università della Florida, siamo entusiasti della collaborazione con GoFAR di questa portata; ciò consente di ridurre la distanza che ci separa dallo sviluppo clinico” ha dichiarato David R. Nelson, MD:, Assistant Vice President Research and Director del CTSI. “La collaborazione tra accademici e associazioni dei pazienti è il fondamento per sviluppare terapie innovative per le malattie rare”. UF: il Powell Gene Therapy Center dell’ Università della Florida è leader mondiale nel campo della terapia genica, avendo condotto con successo trials nei disordini ereditari della retina, nella malattia di Pompe e relativi disturbi neuromuscolari a essa connessi. I ricercatori dell’ UF sono stati pionieri dell’ uso come vettore di varianti non pericolose dei virus adeno-associati, usati per trasportare copie corrette dei geni dove necessitano. GoFAR: Il Comitato RUDI è un’associazione ONLUS di volontari registrata in Italia (n.7603044400-1, Torino), dedicata a favorire e promuovere la ricerca scientifica per la cura dell’ Atassia di Friedreich. Per maggiori informazioni su GoFAR, visitare Contatto: Filomena D’Agostino (Mina), Per la richiesta di informazioni da parte dei media negli U.S., contattare Mindy Cameron al 317-853-6294 o inviare una email a Per la richiesta di informazioni da parte dei media in EU, contattare Annaluisa Ponchia al +39 339 562 3766 o inviare una email a



USF Health and FARA to host patient-focused scientific symposium Sept. 15 [Video]

Written by Anne DeLotto Baier · September 12, 2016 @ 9:59 am · Filed under Hot NewsMorsani College of MedicineNews ReleasesPatient CarePhysical TherapyResearch

International experts from academia and industry will gather to discuss advances in Friedreich’s ataxia from the laboratory to the clinic.

Tampa, FL (Sept. 12, 2016) — The University of South Florida (USF) will bring together leading researchers and patients searching for a treatment for Friedreich’s ataxia (FA) and related disorders at the eighth annual scientific symposium “Understanding Energy for A Cure.” The symposium will be held 5 to 8:30 p.m., Thursday, Sept. 15, at the USF Sam and Martha Gibbons Alumni Center, 11810 USF Alumni Drive, Tampa, FL 33620.

The event, free and open to the public, is hosted by the Friedreich’s Ataxia Research Alliance (FARA) and theUSF Ataxia Research Center.

The symposium will include four scientific panel discussions moderated by FARA spokesperson Kyle Bryant. The topics will be:

Basic and Discovery Science Drug Development and Advancing Treatments FA Biomarkers Clinical Trials and Translating Treatments to Improved Care



Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

1.  Maya Kuperberg, MD1

2.  Dorit Lev, MD2

3.  Lubov Blumkin, MD1

4.  Ayelet Zerem, MD3

5.  Mira Ginsberg, MD3

6.  Ilan Linder, MD3

7.  Nirit Carmi, MD3

8.  Sarah Kivity, MD3

9.  Tally Lerman-Sagie, Prof1

10. Esther Leshinsky-Silver, PhD4

1.   1Metabolic-Neurogenetic Service, Wolfson Medical Center, Holon, Israel

2.   2Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel

3.   3Department of Pediatric Neurology, Wolfson Medical Center, Holon, Israel

4.   4Molecular Genetics laboratory, Wolfson Medical Center, Holon, Israel

1.   Maya Kuperberg, MD, Metabolic-Neurogenetic Service, Wolfson Medical Center, Ha-Lokhamim 62, 58100 Holon, Israel. Email:


Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of “Magen” neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. Genetic databases were updated accordingly. In conclusion, whole exome sequencing is useful in obtaining a high detection rate for previously undiagnosed disorders. Use of this technique could affect diagnosis, treatment, and prognostics for both patients and relatives.




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