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

Comprehensive Analysis of Gene Expression Patterns in Friedreich’s Ataxia Fibroblasts by RNA Sequencing Reveals Altered Levels of Protein Synthesis Factors and Solute Carriers

Napierala JS, Li Y, Lu Y, Lin K, Hauser LA, Lynch DR, Napierala M; University of Alabama at Birmingham, Accession: PRJNA412241, National Center for Biotechnology Information, GEO: the Gene Expression Omnibus. Public on Sep 27, 2017

We used RNA sequencing to profile the transcriptomes of primary fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Transcriptome profiling of FRDA skin fibroblasts revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in the FRDA cells. Finally, comparison of genes differentially expressed in FRDA fibroblasts to 3 previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease.

Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment

Elena Britti, Fabien Delaspre, Anat Feldman, Melissa Osborne, Hagar Greif, Jordi Tamarit, Joaquim Ros; J. Cell. Mol. Med. Vol XX, No X, 2017 pp. 1-15 doi: 10.1111/jcmm.13365

In mice models of the disease, administration of TAT-MTScs-FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT-MTScs-FXN as a treatment for Friedreich ataxia.

The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population

Jonathan F. Plehn, Keren Hasbani, Inez Ernst, Kenneth D. Horton, Bart E. Drinkard, Nicholas A. Di Prospero, Journal of Cardiac Failure, Available online 3 October 2017, ISSN 1071-9164, doi:10.1016/j.cardfail.2017.09.012.

A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.
In our pediatric cohort, GAA repeat length on either allele failed to correlate with LVMI or with measures of systolic or diastolic LV function. These findings are consistent with those of others, two or which were based on robust cMRI criteria. We did note a non-significant trend in GAA repeat length on the long allele with increasing categorical severity of LV remodeling. Despite the high prevalence of ventricular remodeling and functional associations described in this population, there is no evidence to date that early pharmacologic intervention can prevent or impede development of ventricular and/or clinical deterioration.

Urinary, bowel and sexual symptoms in a cohort of patients with Friedreich’s ataxia

Meher Lad, Michael H. Parkinson, Myriam Rai, Massimo Pandolfo, Petya Bogdanova-Mihaylova, Richard A. Walsh, Sinéad Murphy, Anton Emmanuel, Jalesh Panicker† and Paola Giunti; Orphanet Journal of Rare Diseases 201712:158 doi:10.1186/s13023-017-0709-y

Pelvic symptoms are distressing symptoms experienced by patients with Friedreich’s Ataxia (FRDA). The aim of this study was to describe the prevalence of lower urinary tract symptoms (LUTS), bowel and sexual symptoms in FRDA.
A high proportion of FRDA have symptoms suggestive of LUTS, bowel and sexual dysfunction. This is more marked with greater disease duration and later disease onset. These symptoms need to be addressed by clinicians as they can have a detrimental effect on patients.