PATENT: METHODS AND PHARMACEUTICAL COMPOSITION FOR THE TREATMENT AND THE PREVENTION OF CARDIOMYOPATHY DUE TO ENERGY FAILURE

Bibliographic data: US2016024526 (A1) ― 2016-01-28
Inventor(s): PUCCIO HELENE MONIQUE [FR]; AUBORG PATRICK [FR]; CRYSTAL RONALD G [US]; BOUGNERES PIERRE [FR]
Applicant(s): APHP ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS [FR]; UNIV CORNELL [US]; INST NAT SANTE RECH MED [FR]; CENTRE NAT RECH SCIENT [FR]; UNIV STRASBOURG [FR]; UNIVERSITÉ PARIS SUD XI [FR]

The invention relates to a method for preventing or treating a cardiomyopathy associated with Friedreich ataxia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a vector which comprises a frataxin (FXN) encoding nucleic acid.

Role of iron in neurodegenerative diseases

Kai Li, Heinz Reichmann; Neurology and Preclinical Neurological Studies - Review Article, Journal of Neural Transmission pp 1-11 First online: 21 January 2016 DOI: 10.1007/s00702-016-1508-7

 This review summarize recent developments on iron dyshomeostasis in Parkinson’s disease, Alzheimer’s disease, Friedreich ataxia, and Huntington’s disease.

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 Disorders 2015 2:14 DOI: 10.1186/s40734-015-0025-4

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Saccades may be very useful diagnostically in recessive forms of cerebellar ataxia. In Friedreich’s ataxia, prominent fixation instability may take the form of macrosaccadic oscillations or nearly continuous square wave jerks, while interestingly cerebellar atrophy is not seen until the very late stages of the illness.

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

Noemí Esteras, Albena T. Dinkova-Kostova, Andrey Y. Abramov; Biological Chemistry. ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2015-0295, January 2016

Currently, REATA Pharmaceuticals has initiated a clinical trial with a novel Nrf2 activator, named RTA 408, for the treatment of Friedreich’s ataxia (ClinicalTrials.gov, NCT02255435). This neurodegenerative disease is caused by deficiency of the protein frataxin, which causes the disruption of iron-sulphur cluster biosynthesis, mitochondrial iron overload and an increased sensitivity to oxidative stress, mainly due to a decrease in the expression of Nrf2.

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

Dulmini P. Barupala, Stephen P. Dzul, Pamela Jo Riggs-Gelasco, Timothy L. Stemmler, Archives of Biochemistry and Biophysics, Available online 16 January 2016, ISSN 0003-9861, doi:10.1016/j.abb.2016.01.010.


With an incidence of 1 in 50,000172,173, and a carrier prevalence of 1 in 100174, Friedreich’s ataxia (FRDA) is by far the most prevalent disease linked to defective Fe-S cluster formation.
FRDA is an autosomal recessive genetic disease caused by a GAA-trinucleotide repeat expansion in an intron of the frataxin gene, a protein involved in the ISC pathway.

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

Maryleen K. Jones, Stephanie A. Combs-Miller, Archives of Physical Medicine and Rehabilitation, Volume 97, Issue 2, February 2016, Pages 341-342, ISSN 0003-9993, doi:10.1016/j.apmr.2015.04.002.

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 Rehabilitation201613:1 DOI: 10.1186/s12984-015-0109-2

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Many patients with nystagmus (involuntary eye movements) suffer from blurred vision, unstable visual perception and decreased visual acuity (VA), which leads to a decreased quality of life. The etiologies of DBN are diverse.
This study provides proof of concept that non-invasive real-time computer-based visual feedback compensates for the SPV (slow phase velocity) in DBN. Therefore, real-time visual feedback may be a promising aid for patients suffering from oscillopsia and impaired text reading on screen.

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

Maria Stamelou MD, PhD, Movement Disorders, Volume 31, Issue 1, pages 7–8, January 2016, DOI: 10.1002/mds.26508

One should not forget that FA may present later in life with a predominant nonataxic phenotype, such as with a Huntington’s disease phenocopy. Moreover, future studies should provide larger number of patients and more detailed clinical information on further neurological signs such as cognition or autonomic function.

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

ClinicalTrials.gov Identifier: NCT02660112
Sponsor: Ralitza Gavrilova
Collaborator: Cardero Therapeutics, Inc.
Information provided by (Responsible Party): Ralitza Gavrilova, Mayo Clinic
First received: January 18, 2016

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.

Emerging therapies in Friedreich's ataxia

Tanya V Aranca, Tracy M Jones, Jessica D Shaw, Joseph S Staffetti, Tetsuo Ashizawa, Sheng-Han Kuo, Brent L Fogel, George R Wilmot, Susan L Perlman, Chiadi U Onyike, Sarah H Ying & Theresa A Zesiewicz; Neurodegenerative Disease Management Vol. 6, No. 1, Pages 49-65 , DOI 10.2217/nmt.15.73

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.

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

DOWNINGTOWN, Pa. & CAMBRIDGE, Mass.--(BUSINESS WIRE), January 19, 2016
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.
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.

Pediatric cardiac transplantation for Non-dilated cardiomyopathies

Linda J. Addonizio, Progress in Pediatric Cardiology, Available online 16 January 2016, ISSN 1058-9813, doi:10.1016/j.ppedcard.2016.01.006.

In data from the Pediatric Cardiomyopathy Registry, the idiopathic and familial types comprised 74% of the total cases of hypertrophic cardiomyopathy with inborn errors of metabolism comprising 9%(34% of these had Pompe disease), malformation syndromes 9% (78% had Noonan Syndrome) and neuromuscular disorders 8% (88% Friedreich ataxia). Children with inborn errors of metabolism and malformation syndromes have significantly worse outcomes than children with either idiopathic or neuromuscular disease as an etiology for their hypertrophic cardiomyopathy.

The involvement of patient organisations in rare disease research: a mixed methods study in Australia

Deirdre Pinto, Dominique Martin and Richard Chenhall. Orphanet Journal of Rare Diseases 2016, 11:2 doi:10.1186/s13023-016-0382-6

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Acquired Pulmonary Vein Isolation in a Patient with Friedreich Ataxia

Matthew M. Zipse, Ryan G. Aleong, Cardiac Electrophysiology Clinics, Available online 13 January 2016, ISSN 1877-9182, doi: 10.1016/j.ccep.2015.10.016.

This extreme example of atrial fibrosis emphasizes the need to address non-PV substrate, even if AF has only been paroxysmal, in some patients undergoing catheter ablation of AF.

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, Sandra Leistner Segal, Walter O. Arruda, Maria Luiza Saraiva-Pereira, Simone Karuta, José Luiz Pedroso, Anelyssa D’Abreu, Laura B. Jardim, Íscia Lopes-Cendes, Orlando G. Barsottini, Hélio A. G. Teive, Marcondes C. França Jr; Cerebellum. 2016 Jan 11. [Epub ahead of print] DOI:10.1007/s12311-015-0755-8

"LOFA" contradicts several of the classical clinical features of FDRA by this reaon is an important diagnostic challenge for general neurologists

Some interesting data on prevalence: In this study LOFA cases accounted for 17 % of the FDRA patients (Brasil). Other studies found 17 % of LOFA prevalence, and in other the prevalence of LOFA patients ranged from 13.5 to 25%.

Friedreich Ataxia and nephrotic syndrome: a series of two patients

Julianna E. Shinnick, Charles J. Isaacs, Sharon Vivaldi, Kimberly Schadt and David R. Lynch. BMC Neurology201616:3 DOI: 10.1186/s12883-016-0526-2

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

Jupiter, FL (PRWEB) January 12, 2016

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. The product, JOT101, will be a novel proprietary formulation developed by JOT utilising the active ingredient of resveratrol.

Indy drug firm Chondrial scores multi-million-dollar help from NIH Indy drug firm scores multi-million-dollar help from NIH

Indianapolis Business Journal, J.K. Wall, January 13, 2016


Chondrial, which is developing a drug for a rare condition known as Friedreich’s ataxia, will announce Wednesday that it has been accepted into a program run by the National Institutes of Health in which the NIH’s own researchers conduct tests on Chondrial’s drug and pay for outside contractors as needed.
Chondrial’s goal is to apply with the U.S. Food and Drug Administration as early April to get approval for human testing of its drug.

Post-translational modifications in neurodegeneration

Alessandro Didonna, Federico Benetti. AIMS Biophysics, 2016, 3(1): 27-49. doi: 10.3934/biophy.2016.1.27

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A example is Friedreich ataxia, the expanded repeat induces gene silencing through a process of heterochromatinization partially mediated by hypo-acetylation of specific lysine residues on histones around the trinucleotide repeats and on the promoter.
Acetylation is one of the most common PTMs and consists in the reversible transfer of an acetyl group from the acetyl-coenzyme A to the ɛ-amino group of the side chain of lysine residues. Two classes of enzymes catalyze this PTM: histone acetyl transferases (HATs) and histone de-acetylases (HDACs).

Epigenetics and Triplet-Repeat Neurological Diseases

Sathiji Nageshwaran and Richard Festenstein, (Review article) Front. Neurol., 21 December 2015 doi: 10.3389/fneur.2015.00262

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Triplet-Repeat Diseases and Epigenetics: Friedreich’s Ataxia, over 98% of cases are the result of a (GAA)n triplet-repeat expansion within intron 1 of the frataxin (FXN) gene, the rest being the result of compound heterozygosity with an expansion on one allele and a point mutation or insertion on the other........ There is no evidence that frataxin itself is dysfunctional in FRDA, with no defect in mRNA half-life or splicing between patients and unaffected individuals......

Annapurna Therapeutics (formerly AAVLife SAS) to Collaborate with Weill Cornell Medicine on Gene-Therapy Portfolio

PARIS & NEW YORK--(BUSINESS WIRE)--Annapurna Therapeutics today announced a collaboration with Weill Cornell Medicine to build a market-leading gene-therapy company. January 05, 2016

Annapurna, formerly AAVLife SAS, will also continue to fully resource its earlier development of a gene therapy for cardiomyopathy associated with Friedreich’s ataxia. Annapurna is doing observational studies in Friedreich’s ataxia patients to determine appropriate measures for safety and efficacy trials.

Annapurna holds an exclusive worldwide license to a recently issued United States patent covering the use of an AAV vector in gene therapy for cardiomyopathy associated with Friedreich’s ataxia.

Using stem cells to battle brain diseases

Esther B. E. Becker, Atlas of Science


Although scientific progress is being made, neurodegenerative diseases remain incurable. Research into these diseases has been hindered by the inaccessibility of the affected nerve cells in the human brain. However, the recent development of induced pluripotent stem cell (iPSC) technology in 2006 has revolutionized the way in which we can study brain disorders.
Of the small number of studies published to date, most have focused on Friedreich’s ataxia (the most common inherited ataxia).
With constant advances in our understanding of the use of chemicals to mimic embryonic differentiation pathways, it is only a matter of time before these models become a reality.

Publication: Induced pluripotent stem cell technology for modelling and therapy of cerebellar ataxia.Watson LM, Wong MM, Becker EB., Open Biol. 2015 Jul;5(7):150056. doi: 10.1098/rsob.150056.,

2,2′-dipyridyl induces pexophagy

Ai Lin Jin, Joon No Lee, Min Soo Kim, SeongAe Kwak, Se-Jin Kim, Kyung Song, Seong-Kyu Choe, Raekil Park, Biochemical and Biophysical Research Communications, Available online 23 December 2015, ISSN 0006-291X, doi:10.1016/j.bbrc.2015.12.098.

The strictly controlled metabolism of iron is essential, as deficiency or deregulation of iron-related molecules and proteins can cause severe health problems. Friedreich’s ataxia (FRDA) is a common inherited recessive ataxia. Frataxin deficiency causes dysfunction of iron metabolism in mitochondria. A recent report proposed that mitochondrial autophagy (mitophagy) is induced by mitochondrial stress resulting from a defect of iron metabolism-linked reduced frataxin expression.

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

Beutler BD, Cohen PR; Dermatol Pract Concept. 2015 Oct 31;5(4):59-64. doi: 10.5826/dpc.0504a15. eCollection 2015.

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. 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.