Referencias científicas

  

Artículos copiados de diversas fuentes 

 
 

 

 http://link.springer.com/article/10.1007%2Fs00702-016-1508-7

Role of iron in neurodegenerative diseases

·        Kai Li 

·        , Heinz Reichmann

Abstract

Currently, we still lack effective measures to modify disease progression in neurodegenerative diseases. Iron-containing proteins play an essential role in many fundamental biological processes in the central nervous system. In addition, iron is a redox-active ion and can induce oxidative stress in the cell. Although the causes and pathology hallmarks of different neurodegenerative diseases vary, iron dyshomeostasis, oxidative stress and mitochondrial injury constitute a common pathway to cell death in several neurodegenerative diseases. MRI is capable of depicting iron content in the brain, and serves as a potential biomarker for early and differential diagnosis, tracking disease progression and evaluating the effectiveness of neuroprotective therapy. Iron chelators have shown their efficacy against neurodegeneration in a series of animal models, and been applied in several clinical trials. In this review, we summarize recent developments on iron dyshomeostasis in Parkinson’s disease, Alzheimer’s disease, Friedreich ataxia, and Huntington’s disease.

 

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

S0006291X15311037

2,2′-dipyridyl induces pexophagy

·        AiLin Jina, 1, 

·        Joon No Leea, 1, 

·        Min Soo Kima, 

·        SeongAe Kwakb, 

·        Se-Jin Kima, 

·        Kyung Songc, d, 

·        Seong-Kyu Choea, d, , , 

·        Raekil Parka, , 

Abstract

Pexophagy is the selective degradation of peroxisomes for maintaining peroxisome homeostasis within cells. Peroxisome dynamics and pexophagy are important events required to maintain the quality control of peroxisomes, thereby preventing peroxisome-associated diseases. To identify novel pexophagy modulators, we developed a cell-based screening system and selected 2,2′-dipyridyl (2,2-DP) as a candidate molecule. 2,2-DP treatment induced peroxisome degradation as evidenced by an increased number of low-pH autolysosomes originating from peroxisomes and a decrease in the expression of peroxisomal proteins such as catalase, Pex14, and PMP70. The phenotype was defined as pexophagy, because 2,2-DP induced autophagy and inhibition of autophagy significantly reduced the degree of peroxisome degradation. Mechanistically, 2,2-DP-dependent pexophagy seemed to be mediated by iron chelation, since another iron chelator displayed a similar effect on pexophagy, but a copper chelator did not. Notably, iron replenishment prevented 2,2-DP-mediated pexophagy. Taken together, our results suggest that 2,2-DP treatment disrupts peroxisome dynamics and promotes pexophagy through iron depletion.

 

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http://www.ncbi.nlm.nih.gov/pubmed/26693094?dopt=Abstract

Pseudocyst of the auricle in patients with movement disorders: report of two patients with ataxia-associated auricular pseudocysts.

Beutler BD1, Cohen PR2.

Author information

Abstract

BACKGROUND:

Pseudocyst of the auricle is a benign condition of the ear characterized by an asymptomatic, noninflammatory swelling on the lateral or anterior surface of the auricle. It typically presents as a 1 to 5 centimeter cystic lesion located within the scaphoid or triangular fossa. In most patients, the lesion develops spontaneously. However, pseudocyst of the auricle has also been associated with trauma to the ear.

PURPOSE:

We describe the clinical findings of two men who developed pseudocyst of the auricle associated with ataxia-induced trauma to their ear. We also summarize the differential diagnosis, the postulated pathogenesis, and the treatment options for this condition.

MATERIALS AND METHODS:

The features of two men with pseudocyst of the auricle are presented. Using PubMed, the following terms were searched and relevant citations assessed: ataxia, auricle, dyskinesia, ear, Friedreich's, neurological, pinna, pseudocyst, spasticity, spinocerebellar, and trauma. In addition, the literature on pseudocyst of the auricle is reviewed.

RESULTS:

Pseudocyst of the auricle was observed in two men with neurological disorders: a 33-year-old Asian man with spinocerebellar ataxia and a 47-year-old Caucasian man with Friedreich's ataxia. Each patient had a history of ataxia-induced head and ear trauma. The clinical features of the lesions were sufficient to establish a diagnosis of pseudocyst of the auricle. Neither patient desired treatment.

CONCLUSION:

Pseudocyst of the auricle is a benign cystic lesion that is occasionally precipitated by trauma to the affected ear. Patients with neurological disorders, particularly those associated with ataxia and/or dyskinesias, may have an increased risk of developing the traumatic variant of the condition. Diagnosis can usually be established by clinical presentation. However, in some patients, a tissue specimen may be secured for microscopic evaluation to exclude infection or during surgical repair. Various treatment options exist for pseudocyst of the auricle, including: (1) needle aspiration-with or without subsequent injection of an irritant substance-followed by a pressure dressing and (2) surgical deroofing. Alternatively, reassurance of the benign nature of the condition and observation is a reasonable management alternative.

 

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http://www.tandfonline.com/doi/abs/10.3109/

09638288.2015.1106599?journalCode=idre20#

Rare diseases: matching wheelchair users with rare metabolic, neuromuscular or neurological disorders to electric powered indoor/outdoor wheelchairs (EPIOCs)

Abstract

Purpose: To describe the clinical features of electric powered indoor/outdoor wheelchair (EPIOC) users with rare diseases (RD) impacting on EPIOC provision and seating. Method: Retrospective review by a consultant in rehabilitation medicine of electronic and case note records of EPIOC recipients with RDs attending a specialist wheelchair service between June 2007 and September 2008. Data were systematically extracted, entered into a database and analysed under three themes; demographic, diagnostic/clinical (including comorbidity and associated clinical features (ACFs) of the illness/disability) and wheelchair factors. Results: Fifty-four (27 male) EPIOC users, mean age 37.3 (SD 18.6, range 11–70) with RDs were identified and reviewed a mean of 64 (range 0–131) months after receiving their wheelchair. Diagnoses included 27 types of RDs including Friedreich’s ataxia, motor neurone disease, osteogenesis imperfecta, arthrogryposis, cerebellar syndromes and others. Nineteen users had between them 36 comorbidities and 30 users had 44 ACFs likely to influence the prescription. Tilt-in-space was provided to 34 (63%) users and specialised seating to 17 (31%). Four users had between them complex control or interfacing issues. Conclusions: The complex and diverse clinical problems of those with RDs present unique challenges to the multiprofessional wheelchair team to maintain successful independent mobility and community living.

 

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http://journal.frontiersin.org/article/10.3389/

fneur.2015.00262/full

Epigenetics and Triplet-Repeat Neurological Diseases

imageSathiji Nageshwaran and  imageRichard Festenstein*

·        Division of Brain Sciences and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK

The term “junk DNA” has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy’s disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases.

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http://www.prweb.com/releases/2016/01/prweb13155181.htm


Jupiter Orphan Therapeutics, Inc. Enters into a Global Licensing Agreement with Murdoch Childrens Research Institute

 

Jupiter Orphan Therapeutics, Inc. (JOT) today announced that they have entered into a global development and license agreement with Murdoch Childrens Research Institute, Australia’s largest child health research institute. The agreement will see the parties jointly develop an appropriate delivery system and conduct clinical trials with the purpose of getting a product approved for the treatment of Friedreich’s Ataxia.

Friedreich’s Ataxia is an inherited life-shortening disease that causes progressive damage to the nervous system resulting in those affected becoming increasingly unsteady until they require the use of a wheelchair. There are currently no proven treatments.

Murdoch Childrens’ Professor Martin Delatycki is the head of the largest Friedreich’s Ataxia clinic in the southern hemisphere, and his intellectual input and design of clinical trials is central to the agreement.

The product, JOT101, will be a novel proprietary formulation developed by JOT utilising the active ingredient of resveratrol - a natural compound present in grapes and red wine.

Initial studies done by Murdoch Childrens show that this agent has great promise – it was recently found that resveratrol increases a protein called frataxin, which is deficient in the cells of people with Friedreich’s Ataxia. An open-label clinical trial in Friedreich’s Ataxia patients found that there was improvement of neurological symptoms but there were also adverse side effects that limited dosing, meaning a more appropriate formulation and delivery system must be devised.

“There are no treatments that can slow the inexorable progression of this devastating disease. If we can show that JOT101, an improved formulation of resveratrol, is safe, well-tolerated and slows the progression or even reverses some of the symptoms, this would be a significant advancement for people with Friedreich’s Ataxia,” says Prof Delatycki. “Our collaboration with Jupiter Orphan Therapeutics gives us the greatest chance of achieving this.”

“The Friedreich’s Ataxia Research Alliance (FARA) has supported much of the pre-clinical and clinical research that Prof Delatycki and his team at Murdoch Childrens has advanced on resveratrol. We are excited that Jupiter has a new formulation, JOT101, so that we can overcome some of the existing roadblocks and fully evaluate the potential efficacy of resveratrol,” says Jennifer Farmer, Executive Director of FARA.

Jupiter Orphan Pharmaceuticals, Inc. was recently formed to address rare diseases caused by, or related to, single gene deficiencies.

JOT co-founders Christer Rosén and Claes Wahlestedt, jointly stated: “We are very pleased and excited about working together with Prof Delatycki and the Murdoch Childrens’ team with their vast experience in this area. With the addition of JOT’s scientific, clinical, regulatory and formulation expertise we believe that we can, together with Murdoch Childrens, within a relatively short time frame identify a breakthrough treatment for this very serious disease.”

Media contact:

Caitlin Moore - +61 3 8341 6245 or 
Anna Curran - +61 3 9936 6737
 
+61 400 505 090, , Murdoch Childrens Research Institute
 
anna(dot)curran(at)mcri(dot)edu(dot)au

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

http://www.aimspress.com/article/10.3934/biophy.2016.1.27

Post-translational modifications in neurodegeneration

Alessandro Didonna1,  http://www.aimspress.com/web/images/REcor.gif,  http://www.aimspress.com/web/images/REemail.gif, Federico Benetti2,  http://www.aimspress.com/web/images/REcor.gif,  http://www.aimspress.com/web/images/REemail.gif

1 Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA
2 ECSIN-European Center for the Sustainable Impact of Nanotechnology, Viale Porta Adige 45, I-45100 Rovigo, Italy

Post-translational modifications increase proteome functionality for managing all aspects of normal cell biology. They are based on the covalent attachment of functional groups, leading to phosphorylation, acetylation, glycosylation, acylation, ubiquitination, SUMOylation and oxidation of protein targets. Post-translational modifications occur at any step of protein life cycle, modulating in time and space protein folding, subcellular localization and activity. Aberrant post-translational modifications of one or more culprit proteins may lead to neurodegeneration, as shown in paradigmatic neurological disorders such as Alzheimer’s, Parkinson’s and prion diseases. In this review, we report the most important post-translational modifications found in neurodegenerative disorders, illustrating the pathophysiological mechanisms in which they are involved. This work highlights the lack of a global framework of post-translational modifications in terms of complexity and regulation. Therefore, in the next future many efforts are required to describe the interplay existing between post-translational modifications and their combinatorial patterns on protein targets.

 

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

S1058981316000072

Pediatric cardiac transplantation for Non-dilated cardiomyopathies

·        Linda J. Addonizio, 

 Show more

Abstract

Cardiomyopathy is the leading diagnosis for pediatric heart transplantation in children over 1 year of age. The majority of these patients usually have dilated cardiomyopathy. Children with hypertrophic and restrictive types of cardiomyopathy comprise less than 20% of the total children transplanted. Hypertrophic cardiomyopathy is the smallest subgroup to receive a cardiac transplant (6%). The mean age at listing in the Pediatric Heart Transplant Study (PHTS) was 7.6 years, however, 39% were infants listed at a mean of 3.2 + 2.8 months of age. A patient with hypertrophic cardiomyopathy older than 1 year had low waitlist mortality and survival after transplant was no different than dilated or non-cardiomyopathy patients. The infant subgroup had the poorest overall survival with waitlist mortality of 33%, within a few months after listing. Restrictive cardiomyopathy is the rarest type of cardiomyopathy (2–5%) but accounts for 11% of children transplanted with cardiomyopathy in PHTS. Survival after listing in infants < 1 year of age with either hypertrophic or restrictive cardiomyopathy were poor, 50% at 1 year compared with 80% in infants with dilated cardiomyopathy. The mean age at listing for restrictive patients in PHTS was 8.1 years, 81% were transplanted and 9% died waiting (40% of pre-transplant deaths were infants < 1 year). The 1 and 5 year survival was 89 and 77%, similar to other cardiomyopathy patients and better than non-cardiomyopathy patients. Risk factors and clinical profiles leading to listing are discussed.

 

------------------------------------------------------------------------------http://link.springer.com/article/10.1007/s12311-015-0755-8
Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes

·        Alberto R. M. Martinez

·        , Adriana Moro

·        , Agessandro Abrahao

·        , Ingrid Faber

·        , Conrado R. Borges

·        ,Thiago J. R. Rezende

·        , Carlos R. MartinsJr

·        , Mariana Moscovich

·        , Renato P. Munhoz

·         and 11 more

Abstract

Friedreich’s ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann–Whitney and Fisher tests to compare means and proportions between groups; pvalues <0.05 were considered significant. LOFA accounted for 17 % (18/106) and cFDRA for 83 % (88/106) of the patients. There were 13 and 48 women in each group, respectively. LOFA patients were significantly older and had smaller GAA expansions. Clinically, LOFA group had a tendency toward lower frequency of diabetes/impaired glucose tolerance (5.8 vs. 17 %, p = 0.29) and cardiomyopathy (16.6 vs. 28.4 %, p = 0.38). Skeletal abnormalities were significantly less frequent in LOFA (scoliosis 22 vs. 61 %, p = 0.003, and pes cavus 22 vs.75 %, p < 0.001) as were spasticity and sustained reflexes, found in 22 % of LOFA patients but in none of the cFDRA patients (p = 0.001). LOFA accounts for 17 % of Brazilian FDRA patients evaluated herein. Clinically, orthopedic features and spasticity with retained reflexes are helpful tips to differentiate LOFA from cFDRA patients.

 

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https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0526-2

Friedreich Ataxia and nephrotic syndrome: a series of two patients

·        Julianna E. Shinnick, 

·        Charles J. Isaacs, 

·        Sharon Vivaldi, 

·        Kimberly Schadt and 

·        David R. Lynch

Background

Friedreich Ataxia (FRDA) is a neurodegenerative disorder characterized by gait and balance abnormalities, sensory loss, weakness, loss of reflexes, and ataxia. Previously, two cases of FRDA and Nephrotic Syndrome (NS) have been reported. Here we report two additional individuals with NS and FRDA, providing further evidence for a possible connection between the two diseases and focusing on the neuromuscular responsiveness of one individual to corticosteroid treatment, an effect not previously described in FRDA.

Case presentations

We describe two patients with FRDA also presenting with NS. The first patient was diagnosed with FRDA at age 5 and NS at age 7 following the development of periorbital edema, abdominal swelling, problems with urination, and weight gain. The second patient was diagnosed with NS at age 2 after presenting with periorbital edema, lethargy, and abdominal swelling. He was diagnosed with FRDA at age 10. Nephrotic syndrome was confirmed by laboratory testing in both cases and both individuals were treated with corticosteroids.

Conclusions

Nephrotic syndrome may occur in individuals with FRDA, but was not associated with myoclonic epilepsy in our patients as previously described. It is unlikely that this association is coincidental given the rarity of both conditions and the association of NS with mitochondrial disease in model systems, though coincidental coexistence is possible. One patient showed neurological improvement following steroid treatment. Although neurological improvement could be attributed to the treatment of NS, we also identified some degree of steroid responsiveness in a series of patients with FRDA but without NS.

 

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http://www.businesswire.com/news/home/20160119005239/

en/

FARA Announces Catabasis Pharmaceuticals as the Recipient of the Kyle Bryant Translational Research Award to Evaluate CAT-4001 as a Potential Therapy for Friedreich’s Ataxia

January 19, 2016 08:00 AM Eastern Standard Time

DOWNINGTOWN, Pa. & CAMBRIDGE, Mass.--(BUSINESS WIRE)--The Friedreich’s Ataxia Research Alliance (FARA) and Catabasis Pharmaceuticals, Inc. (NASDAQ:CATB) announce that Catabasis Pharmaceuticals is the recipient of the Kyle Bryant Translational Research Award. Catabasis is a clinical-stage drug development company built on a pathway pharmacology technology platform. The two year award will be for the Evaluation of CAT-4001 in Frataxin-deficient mouse models and dorsal root ganglia neurons to enable its therapeutic development for Friedreich's ataxia. This work will be led by Dr. Andrew Nichols at Catabasis along with collaborators Dr. Mark Payne at Indiana University and Dr. Jordi Magrane at Weill Cornell College of Medicine who are expected to perform testing in the Friedreich’s ataxia (FA) animal models.

“We are sensitive to the unmet medical need for patients affected by Friedreich’s ataxia and believe partnerships such as this could make a meaningful difference in discovering and developing therapies for them.”

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Catabasis is developing CAT-4001 as a potential treatment for neurodegenerative diseases such as FA. CAT-4001 is designed to activate Nrf2 and inhibit NF-kB, both of which are implicated in FA pathophysiology. Catabasis has shown that CAT-4001 modulates the Nrf2 and NF-kB pathways in both cellular assays and animal models.

“We are excited to support this research as it brings a potential new candidate to the FA treatment pipeline and the research development team advancing the work is an example of FARA’s private public partnership strategy. We believe that we make the most meaningful research advancements when FARA, our academic investigators and our pharmaceutical partners take a collaborative approach to answering research questions,” said FARA Executive Director, Jennifer Farmer.

The Kyle Bryant Translational Research Award specifically focuses on pre-clinical and clinical investigations that target treatments for FA. The award is named for a young man diagnosed in his early teens with FA, Kyle Bryant, who started a cycling program called rideATAXIA with his family in 2007. The named award not only honors Kyle’s initiative to do his part to advance FA research but also recognizes all FA families involved in fundraising for research.

“We greatly appreciate the support of the Friedreich’s Ataxia Research Alliance as we advance the preclinical development of CAT-4001 as a candidate to treat FA,” said Andrew Nichols, PhD, Catabasis Senior Vice President, Research and Non-Clinical Development. “We are sensitive to the unmet medical need for patients affected by Friedreich’s ataxia and believe partnerships such as this could make a meaningful difference in discovering and developing therapies for them.”

About FA

Friedreich’s ataxia is a rare, degenerative, life-shortening neuro-muscular disorder that affects children and adults, and involves the loss of strength and coordination usually leading to wheelchair use; diminished vision, hearing and speech; scoliosis (curvature of the spine); increased risk of diabetes; and a life-threatening heart condition. There are no FDA-approved treatments.

About FARA

The Friedreich's Ataxia Research Alliance (FARA) is a 501(c)(3), non-profit, charitable organization dedicated to accelerating research leading to treatments and a cure for Friedreich's ataxia. www.CureFA.org

About CAT-4001

Catabasis is developing CAT-4001 as a potential treatment for neurodegenerative diseases such as Friedreich’s ataxia (FA) and amyotrophic lateral sclerosis (ALS). CAT-4001 is a small molecule that activates Nrf2 and inhibits NF-kB, two pathways that have been implicated in FA and ALS. Catabasis has shown that CAT-4001 modulates the Nrf2 and NF-kB pathways in both cellular assays and animal models.

About Catabasis

Catabasis Pharmaceuticals is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics using its proprietary Safely Metabolized And Rationally Targeted, or SMART, linker technology platform. The Company's SMART linker technology platform is based on the concept of treating diseases by simultaneously modulating multiple targets in one or more related disease pathways. The Company engineers bi-functional product candidates that are conjugates of two molecules, or bioactives, each with known pharmacological activity, joined by one of its proprietary SMART linkers. The SMART linker conjugates are designed for enhanced efficacy and improved safety and tolerability. The Company’s focus is on treatments for rare diseases. The Company is also developing other product candidates for the treatment of serious lipid disorders. For more information on the Company's technology and pipeline of drug candidates, please visit www.catabasis.com.

Contacts

Friedreich's Ataxia Research Alliance
Felicia DeRosa, 484-879-6160
Program Director
info@curefa.org
or
Catabasis Pharmaceuticals, Inc.
Andrea Matthews, 617-349-1971
amatthews@catabasis.com

 

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http://clinicalmovementdisorders.biomedcentral.com/

articles/10.1186/s40734-015-0025-4?utm_campaign=BMC26307D&utm_medium=BMCemail&utm

 

_source=Teradata

The diagnostic value of saccades in movement disorder patients: a practical guide and review

·        Pichet Termsarasab, 

·        Thananan Thammongkolchai, 

·        Janet C. Rucker and 

·        Steven J. Frucht

Journal of Clinical Movement Disorders20152:14

DOI: 10.1186/s40734-015-0025-4

©  Termsarasab et al. 2015

Received: 13 May 2015

Accepted: 1 September 2015

Published: 15 October 2015

Abstract

Saccades are rapid eye movements designed to shift the fovea to objects of visual interest. Abnormalities of saccades offer important clues in the diagnosis of a number of movement disorders. In this review, we explore the anatomy of horizontal and vertical saccades, discuss practical aspects of their examination, and review how saccadic abnormalities in hyperkinetic and hypokinetic movement disorders aid in diagnosis, with video demonstration of classic examples. Documentation of the ease of saccade initiation, range of motion and conjugacy of saccades, speed and accuracy of saccades, dynamic saccadic trajectory, and the presence or absence of saccadic intrusions and oscillations are important components of this exam. We also provide a practical algorithm to demonstrate the value of saccades in the differential diagnosis of the movement disorders patient.

Keywords

Saccade Eye movement Ocular motility Movement disorders

 

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

mds.26508/abstract

Late-onset cerebellar ataxia: Do not forget Friedreich's

https://clinicaltrials.gov/ct2/show/NCT02660112?term=friedreich&rcv_d=14

+) Epicatechin to Treat Friedreich's Ataxia

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

Verified January 2016 by Mayo Clinic

Sponsor:

Ralitza Gavrilova

Collaborator:

Cardero Therapeutics, Inc.

Information provided by (Responsible Party):

Ralitza Gavrilova, Mayo Clinic

ClinicalTrials.gov Identifier:

NCT02660112

First received: January 18, 2016

Last updated: January 18, 2016

Last verified: January 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

This 24-week study will test the safety and effectiveness of synthetically produced (+) Epicatechin in treating patients who have Friedreich's Ataxia, a neurological disorder.

 

Condition

Intervention

Phase

Friedreich's Ataxia

Drug: (+)-Epicatechin

Phase 2

 

Study Type:

Interventional

Study Design:

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

Official Title:

A Phase II, Open Label Prospective Single Center Drug Study Evaluating the Safety and Efficacy of (+)-Epicatechin in Subjects With Friedreich's Ataxia

 

Resource links provided by NLM:

 

Genetics Home Reference related topics: ataxia neuropathy spectrum childhood

 myocerebrohepatopathy spectrum deoxyguanosine kinase

 deficiency Friedreich ataxiamitochondrial neurogastrointestinal 

encephalopathy disease myoclonic epilepsy myopathy sensory 

ataxia

MedlinePlus related topics: Friedreich's Ataxia

Drug Information available for: Cianidanol

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

U.S. FDA Resources 

 

Further study details as provided by Mayo Clinic:

 

Primary Outcome Measures:

·        Change from baseline in Friedreich Ataxia Rating Scale (FARS) composite score [ Time Frame: Baseline, 24 weeks ] [ Designated as safety issue: No ]

The Friedreich Ataxia Rating Scale (FARS) is made up of a measure of ataxia, an activities of daily living subscale and a neurological subscale. This scale also includes the 8m walk at maximum speed (8MW), the 9-hole peg test (9HPT), PATA rate (assesses speech speed) and low-contrast letter acuity.

 

FARS is made up of a measure of ataxia, an activities of daily living subscale and a neurological subscale. This scale also includes the 8m walk at maximum speed (8MW), the 9-hole peg test (9HPT), PATA rate and low-contrast letter acuity. The scores from the three subscales are added to generate a total score ranging from 0 to 159, with a higher score indicating a greater level of disability.

 

·        Change from baseline in ventricular hypertrophy as shown on cardiac MRI [ Time Frame: Baseline, 24 weeks ] [ Designated as safety issue: No ]

 

Estimated Enrollment:

10

Study Start Date:

April 2016

Estimated Study Completion Date:

December 2018

Estimated Primary Completion Date:

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

 

Arms

Assigned Interventions

Experimental: (+)-Epicatechin

Total daily dose 75mg (+)-Epicatechin; 25mg cap three times per day by mouth for 24 weeks

Drug: (+)-Epicatechin

25mg (+)-Epicatechin capsules. Starting dose 75mg total daily dose (one 25mg cap taken three times per day). Dose escalation at 12 weeks for non-responders to 150mg total daily dose (two 25mg caps taken three times per day)



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

Ages Eligible for Study:  

10 Years to 50 Years

Genders Eligible for Study:  

Both

Accepts Healthy Volunteers:  

No

Criteria

Inclusion Criteria:

·        Confirmed diagnosis of Friedreich's Ataxia (FA) by Frataxin genetic testing and/or Frataxin enzyme analysis

·        Between age 10 and 50 years of age, inclusive

·        Body weight of 25 kilograms or higher

·        Minimum of one affected organ (cardiac or neurological) system, as evidenced by clinical signs/symptoms

·        Disease duration ≤7 years, based on onset date of FA symptoms

·        Has no known contraindication to gadolinium contrast such as severe allergy or Glomerular Filtration Rate <30 ml/min/m^2.

·        Has no known contraindication to non-contrast Magnetic Resonance Imaging (MRI) evaluation such as pacemaker or magnetically active metal fragments.

·        Women of childbearing age must:

o   Have a negative pregnancy human chorionic gonadotropin test prior to receiving study drug.

o   Agree to use contraception for the duration of the study drug dosing, plus 1 month after completion of the study.

Exclusion Criteria:

·        Advanced cardiac failure, New York Heart Association (NYHA) Classification Scale-Class IV (advanced stage heart failure)

·        Clinically significant comorbidities that may also lead to cardiomyopathy, for example long standing hypertension, familial cardiomyopathy.

·        Clinically significant comorbidities that would, in the opinion of the investigators, compromise the interpretation of test results.

·        Pregnant, breast-feeding or planning to become pregnant during study timeframe.

·        Patients with contraindications to regadenoson, i. e. second- or third-degree atrioventricular (AV) block or sinus node dysfunction. Has received an investigational drug within thirty (30) days of baseline visit.

·        Thrombocytopenia (<125 x 10^9/Liter) or prolonged Prothrombin Time/Partial Thromboplastin Time (PT/PTT) at baseline.

·        Clinically significant hypotension (systolic blood pressure <90) due to heart failure or other conditions.

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: NCT02660112

Contacts

Contact: Jennifer Kemppainen, MS, CGC

507-266-2967


Contact: Kayla M Ehlenfeldt

507-266-2967



Sponsors and Collaborators

Ralitza Gavrilova

Cardero Therapeutics, Inc.

Investigators

Principal Investigator:

Ralitza H Gavrilova, MD

Mayo Clinic

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


No publications provided 

Responsible Party:

Ralitza Gavrilova, MD, Sponsor-Investigator, Mayo Clinic

ClinicalTrials.gov Identifier:

NCT02660112     History of Changes

Other Study ID Numbers:

15-006845 

Study First Received:

January 18, 2016

Last Updated:

January 18, 2016

Health Authority:

United States: Food and Drug Administration


Additional relevant MeSH terms:

 

Friedreich Ataxia
Ataxia
Brain Diseases
Central Nervous System Diseases
Cerebellar Diseases
Dyskinesias
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System

Metabolic Diseases
Mitochondrial Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurologic Manifestations
Signs and Symptoms
Spinal Cord Diseases

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http://www.futuremedicine.com/doi/abs/

10.2217/nmt.15.73?url_ver=Z39.88-

2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&

Emerging therapies in Friedreich's ataxia

Tanya V Aranca1, Tracy M Jones1, Jessica D Shaw1, Joseph S Staffetti1, Tetsuo Ashizawa3,Sheng-Han Kuo4, Brent L Fogel5, George R Wilmot6, Susan L Perlman7, Chiadi U Onyike8,Sarah H Ying9,10,11 & Theresa A Zesiewicz*,1,2

*Author for correspondence: tzesiewi@health.usf.edu


Friedreich's ataxia (FRDA) is an inherited, progressive neurodegenerative disease that typically affects teenagers and young adults. Therapeutic strategies and disease insight have expanded rapidly over recent years, leading to hope for the FRDA population. There is currently no US FDA-approved treatment for FRDA, but advances in research of its pathogenesis have led to clinical trials of potential treatments. This article reviews emerging therapies and discusses future perspectives, including the need for more precise measures for detecting changes in neurologic symptoms as well as a disease-modifying agent.

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http://jneuroengrehab.biomedcentral.com/

articles/10.1186/s12984-015-0109-2

Real-time computer-based visual feedback improves visual acuity in downbeat nystagmus – a pilot study

·        Julian Teufel

·        S. Bardins, 

·        Rainer Spiegel, 

·        O. Kremmyda, 

·        E. Schneider, 

·        M. Strupp and 

·        R. Kalla

Journal of NeuroEngineering and Rehabilitation

Abstract

Background

Patients with downbeat nystagmus syndrome suffer from oscillopsia, which leads to an unstable visual perception and therefore impaired visual acuity. The aim of this study was to use real-time computer-based visual feedback to compensate for the destabilizing slow phase eye movements.

Methods

The patients were sitting in front of a computer screen with the head fixed on a chin rest. The eye movements were recorded by an eye tracking system (EyeSeeCam®). We tested the visual acuity with a fixed Landolt C (static) and during real-time feedback driven condition (dynamic) in gaze straight ahead and (20°) sideward gaze. In the dynamic condition, the Landolt C moved according to the slow phase eye velocity of the downbeat nystagmus. The Shapiro-Wilk test was used to test for normal distribution and one-way ANOVA for comparison.

Results

Ten patients with downbeat nystagmus were included in the study. Median age was 76 years and the median duration of symptoms was 6.3 years (SD +/- 3.1y). The mean slow phase velocity was moderate during gaze straight ahead (1.44°/s, SD +/- 1.18°/s) and increased significantly in sideward gaze (mean left 3.36°/s; right 3.58°/s). In gaze straight ahead, we found no difference between the static and feedback driven condition. In sideward gaze, visual acuity improved in five out of ten subjects during the feedback-driven condition (p = 0.043).

Conclusions

This study provides proof of concept that non-invasive real-time computer-based visual feedback compensates for the SPV in DBN. Therefore, real-time visual feedback may be a promising aid for patients suffering from oscillopsia and impaired text reading on screen. Recent technological advances in the area of virtual reality displays might soon render this approach feasible in fully mobile settings.

Keywords

Downbeat nystagmus Visual acuity Eye tracking Video oculography Computer-based visual feedback

 

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

pii/S0003999315002993
Measurement Characteristics and Clinical Utility of the International Cooperative Ataxia Rating Scale in Individuals With Hereditary Ataxias
 

·        Maryleen K. Jones, PT, MPT, CLT, NCS, 

·        Stephanie A. Combs-Miller, PT, PhD, NCS

 Show more

Highlights From the Rehabilitation Measures Database

This content is provided as a service by the American Congress of Rehabilitation Medicine and is not peer reviewed by the Archives.

 

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http://www.degruyter.com/view/j/bchm.just-accepted/hsz-2015-0295/hsz-2015-0295.xml

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Noemí Esteras1 / Albena T. Dinkova-Kostova23 / Andrey Y. Abramov1

1Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK

2Jacqui Wood Cancer, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, UK

3Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

 

Abstract

The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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

 

S0003986116300108

Synthesis, Delivery and Regulation of Eukaryotic Heme and Fe-S Cluster Cofactors

·        Dulmini P. Barupalaa, 1

·        Stephen P. Dzula, 1

·        Pamela Jo Riggs-Gelascob

·        Timothy L. Stemmlera, , 

Abstract

In humans, the bulk of iron in the body (over 75%) is directed towards heme- or Fe-S cluster cofactor synthesis, and the complex, highly regulated pathways in place to accomplish biosynthesis have evolved to safely assemble and load these cofactors into apoprotein partners. In eukaryotes, heme biosynthesis is both initiated and finalized within the mitochondria, while cellular Fe-S cluster assembly is controlled by correlated pathways both within the mitochondria and within the cytosol. Iron plays a vital role in a wide array of metabolic processes and defects in iron cofactor assembly leads to human diseases. This review describes progress towards our molecular-level understanding of cellular heme and Fe-S cluster biosynthesis, focusing on the regulation and mechanistic details that are essential for understanding human disorders related to the breakdown in these essential pathways.

 

 

 

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