Recombinant adeno-associated viral vector serotype 5 carrying the gene for the human frataxin protein for the treatment of Friedreich’s ataxia

EU/3/17/1906: Public summary of opinion on orphan designation (First published: 17/10/2017): On 23 August 2017, orphan designation (EU/3/17/1906) was granted by the European Commission to Voisin Consulting S.A.R.L., France, for recombinant adeno-associated viral vector serotype 5 carrying the gene for the human frataxin protein (also known as AGIL-FA) for the treatment of Friedreich’s ataxia.
What is the stage of development of this medicine?:
The effects of the medicine have been evaluated in experimental models.
At the time of submission of the application for orphan designation, no clinical trials with this medicinein patients with Friedreich’s ataxia had been started.
At the time of submission, the medicine was not authorised anywhere in the EU for Friedreich’s ataxia.
Orphan designation of the medicine had been granted in the United States for this condition.

Therapies for mitochondrial diseases and current clinical trials

Ayman W. El-Hattab, Ana Maria Zarante, Mohammed Almannai, Fernando Scaglia, In Molecular Genetics and Metabolism, 2017, , ISSN 1096-7192, doi:10.1016/j.ymgme.2017.09.009.

Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Based on limited number of clinical trials, several agents aiming at enhancing mitochondrial function or treating the consequences of mitochondrial dysfunction have been used. Several agents are currently being evaluated for mitochondrial diseases. Therapeutic strategies for mitochondrial diseases include the use of agents enhancing electron transfer chain function (coenzyme Q10, idebenone, riboflavin, dichloroacetate, and thiamine), agents acting as energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), amino acids restoring nitric oxide production (arginine and citrulline), cardiolipin protector (elamipretide), agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide bypass therapy, liver transplantation, and gene therapy. Although, there is a lack of curative therapies for mitochondrial disorders at the current time, the increased number of clinical research evaluating agents that target different aspects of mitochondrial dysfunction is promising and is expected to generate more therapeutic options for these diseases in the future.

In Vivo Assessment of Mitochondrial Dysfunction in Clinical Populations Using Near-Infrared Spectroscopy

T. Bradley Willingham and Kevin K. McCully, Front. Physiol., 14 September 2017 doi:10.3389/fphys.2017.00689

The ability to sustain submaximal exercise is largely dependent on the oxidative capacity of mitochondria within skeletal muscle, and impairments in oxidative metabolism have been implicated in many neurologic and cardiovascular pathologies. Here we review studies which have demonstrated the utility of Near-infrared spectroscopy (NIRS) as a method of evaluating of skeletal muscle mitochondrial dysfunction in clinical human populations.

In FRDA, NIRS measures of mitochondrial capacity in the forearm were inversely correlated with feelings of low energy, suggesting that mitochondrial function may be related to fatigue in persons with FRDA across the spectrum of symptom severity (Bossie et al., 2016). These findings lend support to the use of NIRS measures of mitochondrial capacity as measure of muscle dysfunction in persons with FRDA during interventions or over the course of disease progression.

There are currently no physiological evaluation tools available for clinicians diagnosing and treating patients with mitochondrial disease, and the application of NIRS may offer a relevant, in vivo measure of mitochondrial function in this population. To date, Friedreich's ataxia is the only mitochondrial disease to be evaluated using NIRS, and establishing the usefulness of NIRS in evaluating mitochondrial dysfunction in persons with mitochondrial disease warrants further investigation.

Estudos moleculares em ataxia de Friedreich

Peluzzo, Thiago Mazzo, Advisor: França Junior, Marcondes Cavalcante; TESE DIGITAL 2017

We therefore designed this study to determine the frequency, phenotypic and mutational profile of Brazilian patients that presented compound heterozygosity for FXN. To accomplish that, we recruited patients from 3 national reference centers (State University of Campinas-UNICAMP, São Paulo University at Ribeirão Preto-USP-RP and Federal University of Rio Grande do Sul-UFRGS). Those patients with a single identified expansion underwent sequencing of all 5 exons and exon-intron boundaries at FXN (Sanger technique). We identified a novel variant (c.482+1G>T) considered pathogenic following American College of Medical Genetics and Genomics (ACMG) guidelines. In addition, another pathogenic variant previously described in the literature (c.157delC) was found in 2 unrelated subjects. Compound heterozygosity accounted for 2.87% (5/174) of all patients; however, when considered only cases in which point mutations were found, the rate decreases to 1,72% (3/174). These are novel data for the Brazilian population. From a clinical perspective, they will help the choice of adequate techniques for FRDA diagnosis and proper genetic counseling in our country.

CRISPR Therapeutics Awarded Grant from Friedreich’s Ataxia Research Alliance to Collaborate with University of Alabama at Birmingham on Gene-edited Treatments for Friedrich’s Ataxia

ZUG, Switzerland and CAMBRIDGE, Mass., Oct. 13, 2017 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (NASDAQ:CRSP), a genome editing company focused on creating transformative medicine for serious diseases, today announced the receipt of the Kyle Bryant Translational Research Award from Friedreich’s Ataxia Research Alliance (FARA), a non-profit organization that is focused on curing Friedreich’s Ataxia (FA). The grant is awarded to fund research on in vivo CRISPR/Cas9-based gene-editing approaches to treat FA, which will be performed in collaboration with Dr. Marek Napierala at University of Alabama at Birmingham. This announcement coincides with FARA’s rideATAXIA Philadelphia event, a lead location in an annual bike ride program founded by patient Kyle Bryant, that increases FA awareness and raises funds to treat and cure FA through research.

FDA awards six grants for natural history studies in rare diseases

12-10-2017. SILVER SPRING, Md: The U.S. Food and Drug Administration today announced it has awarded six new research grants for natural history studies in rare diseases. The aim of the research is to inform medical product development by better understanding how specific rare diseases progress over time.
Grants being funded by the FDA:
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•Children's Hospital of Philadelphia, David Lynch, Prospective study in Friedreich's ataxia, approximately $2 million over 5 years
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Mathematical modeling of Friedreich’s ataxia – a genetic neuro-muscular degenerative condition

SWASTI WAGH and D.K. WAGH; Journal of Ultra Scientist of Physical Sciences, Volume 29, Issue 2, Page Number 66-70, 2017 doi:10.22147/jusps-A/290203

Currently Friedreich’s Ataxia (FA) is not considered an important health problem because of its relatively low prevalence in the general population. However with improvement in health care diagnosis and delivery provisions, more and more people with Friedreich’s Ataxia (FA) are being diagnosed and surviving. This means that its incidence and prevalence is bound to change. We have used a mathematical model to estimate generational increase in the number of patients and carriers with FA. The results portray a scary picture and hence demand measures to take it more seriously by health care providers.

Today Friedreich’s Ataxia is considered to be a rare disease. Being genetic it passes on in offspring. Calculations based on the Mathematical Model reveal that practically in the seventh generation almost 1/4th of the population becomes patient. This is very serious and to avoid this measures must be taken. On the basis of Mathematical Model we can suggest following measures. It follows from matrix B that if a carrier is crossed with the normal, the probability of offspring being patient is zero. Hence if the carrier is not allowed to cross with patient or the carrier the increase in population of patients can be controlled.

The New Zealand Neuromuscular Disease Patient Registry; Five Years and a Thousand Patients.

Rodrigues, Miriam J., O’Grady, Gina, Hammond-Tooke, Graemed, Kidd, Alexaf, Love, Donald O.g, Baker, Ronelle K.b, Roxburgh, Richard H.a; Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 183-188, 2017; DOI: 10.3233/JND-170240

The changing roles of a rare disease patient registry. (a) Ten roles performed by registries along the pathway of treatment development – adapted with permission from Betsy Bogard (see acknowledgements*). (b) The NZ NMD Registry’s current role in the pathway of treatment development for its respective patient populations.

We have demonstrated that an overarching registry serving all neuromuscular diseases managed by a single project team is effective; this is in contrast to countries such as the UK, Spain and Germany where disease-specific registries are commonly deployed but similar to Canada where the Canadian Neuromuscular Disease Registry (CNDR) covers a range of disorders

Friedreich Ataxia: Developmental Failure of the Dorsal Root Entry Zone

Arnulf H. Koeppen, MD Alyssa B. Becker, BA Jiang Qian, MD, PhD Benjamin B. Gelman, MD, PhD Joseph E. Mazurkiewicz, PhD; Journal of Neuropathology & Experimental Neurology, nlx087, doi:10.1093/jnen/nlx087

The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.

Agilis Biotherapeutics Updates on Progress in CNS Gene Therapy Programs

CAMBRIDGE, Mass.--(October 03, 2017)--Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS),

Friedreich Ataxia: The Company’s program in Friedreich ataxia (FA), AGIL-FA, an AAV-based vector for delivery of the human FXN gene intended to address the CNS manifestations of FA, is advancing rapidly through nonclinical, manufacturing and regulatory activities toward human clinical study. Agilis has generated a proprietary library of optimized FXN gene constructs through engineering of promotor and gene regulatory elements tied to the wild-type FXN gene in collaboration with Intrexon Corporation (NASDAQ: XON), resulting in novel compositions of matter and intellectual property. In vitro characterization, including analyses in inducible pluripotent stem cell systems, has verified the critical functional parameters of the optimized FXN gene and frataxin protein, leading to selection of the AGIL-FA lead construct. Analyses of routes of CNS administration and biodistribution of the optimized lead construct using the selected AAV vector have been completed in five in vivo IND-enabling non-clinical studies, demonstrating reproducible targeting of the FXN gene to, and expression of the frataxin protein in, target CNS cells that data suggest are integral to CNS manifestations in FA. The Company has completed a pre-IND meeting with the FDA and is on track to open an IND in 2018