Gene therapy—from small beginnings to where we are now

J C Glorioso and N Lemoine; Gene Therapy (2017) 24, 495–496; doi:10.1038/gt.2017.23

While there have been many hurdles to overcome that relate to safety, immunity and manufacturing, still, the logic of this treatment modality remains intact and most of us in the field believe that it will take its place as a standard of care just as the use of monoclonal antibodies and pharmaceutical drugs of all types has become widely employed. This is especially true for diseases that are too complex to treat with single approaches, such as cancer.
GT is one of the most highly regulated therapeutic fields. There were numerous control bodies formed to understand the long-term impact of gene therapy and to consider the dangers of viral vector engineering and transfer to humans. While the risk inherent in GT success is quite high, the rewards are potentially enormous both from a commercial as well as human medicine point of view.
There are many fields such as organ transplantation technology that have taken many years to develop before they have become standard practice, and no doubt gene therapy will take a similar path. We predict that by mid-century, there will be many GT options for patients, and in combination with other treatment strategies, will move human medicine to reach heights that are currently unanticipated. The challenge will be how to deliver what are now expensive and difficult treatments to people worldwide who have less developed health care systems and wealth. Our sense is that as we create better treatment options, their costs will come down and rival immunization protocols.

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

Celine J. Rocca, Spencer M. Goodman, Jennifer N. Dulin, Joseph H. Haquang, Ilya Gertsman, Jordan Blondelle, Janell L. M. Smith, Charles J. Heyser and Stephanie Cherqui; Science Translational Medicine 25 Oct 2017: Vol. 9, Issue 413, eaaj2347 DOI: 10.1126/scitranslmed.aaj2347

We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.

Can rehabilitation improve the health and well-being in Friedreich’s ataxia: a randomized controlled trial?

Milne SC, Corben LA, Roberts M, Murphy A, Tai G, Georgiou-Karistianis N, Yiu EM, Delatycki MB; Clin Rehabil. 2017 Oct 1:269215517736903. doi: 10.1177/0269215517736903.

Our study indicates that rehabilitation can improve health and well-being in individuals with Friedreich’s ataxia; however, a larger study is required to have sufficient power to detect a significant change in the most sensitive measure of function, the motor domain of the Functional Independence Measure.

Reata Announces First Patient Enrolled in Part 2 of MOXIe Study of Omaveloxolone for the Treatment of Friedreich’s Ataxia

IRVING, Texas, Oct. 23, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (NASDAQ:RETA) (“Reata” or the “Company”) today announced the enrollment of the first patient in the pivotal Part 2 of the MOXIe trial to evaluate omaveloxolone in patients with Friedreich’s ataxia (FA).
Part 2 of the MOXIe trial is a double-blind, randomized, placebo-controlled, multi-center, international trial designed to evaluate the safety, tolerability, and efficacy of omaveloxolone in patients with FA. The trial will enroll approximately 100 FA patients randomized evenly to either 150 mg of omaveloxolone or placebo. The primary endpoint of the trial will be the change from baseline in the modified Friedreich’s Ataxia Rating Scale (mFARS) of omaveloxolone compared to placebo at 48 weeks. Additional endpoints will include the change from baseline in peak work during maximal exercise testing, Patient Global Impression of Change, and Clinical Global Impression of Change. The U.S. Food and Drug Administration has confirmed that use of mFARS as the primary endpoint in Part 2 of the MOXIe trial can support approval of omaveloxolone in FA. Reata expects top-line data to be available in the second half of 2019.

Friedreich’s ataxia: clinical features, pathogenesis and management

A Cook, P Giunti; British Medical Bulletin,  2017, 1–12 doi:10.1093/bmb/ldx034

The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets.
The search for effective disease-modifying agents continues. It remains to be determined whether the most effective approach to treatment lies with increasing frataxin protein levels or addressing the metabolic consequences of the disease, for example with antioxidants.
Management of Freidreich’s ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential.

Incidence et caractéristiques de la scoliose neurologique dans l’ataxie de Friedreich à maturité osseuse

Jean Meyblum, Anne-Laure Simon, Christophe Vidal, Isabelle Husson, Bastien Roche, Brice Ilharreborde, Revue de Chirurgie Orthopédique et Traumatologique, Volume 103, Issue 7, Supplement, November 2017, Page S52, ISSN 1877-0517, doi:10.1016/j.rcot.2017.09.072.

L’incidence de la déformation scoliotique est élevée dans l’AF (74 % de la cohorte). Il n’existe pas de prévalence d’un type particulier de courbure. L’hypercyphose thoracique était fréquemment retrouvée sans être associée à un type de scoliose, témoignant du déséquilibre antérieur de la marche cérébelleuse. L’arthrodèse rachidienne n’a pas fait perdre la marche chez les patients marchant encore au moment de la chirurgie.

Cardiomyopathy in Friedreich’s Ataxia

Pablo Salazar, Raksha Indorkar, Michael Dietrich, Afshin Farzaneh-Far; European Heart Journal, , ehx607, doi:10.1093/eurheartj/ehx607

A 27-year old man with Friedreich’s Ataxia was referred for cardiac evaluation. He had no cardiac symptoms, and his physical exam was remarkable for an ataxic-gait and increased muscle tone.

Nrf2-Inducers Counteract Neurodegeneration in Frataxin-Silenced Motor Neurons: Disclosing New Therapeutic Targets for Friedreich’s Ataxia

Petrillo, S.; Piermarini, E.; Pastore, A.; Vasco, G.; Schirinzi, T.; Carrozzo, R.; Bertini, E.; Piemonte, F.; Int. J. Mol. Sci. 2017, 18, 2173. doi:10.3390/ijms18102173

In FA, the dys-regulation of cellular antioxidant defenses, due to frataxin deficiency, exacerbates oxidative stress, thus the Nrf2 activation becomes more and more of an attractive strategy for the treatment of this disease.

Overall, our findings support Nrf2 as a therapeutic target for FA, and its induction as a promising approach to prevent or slow the pathological changes observed in this disease. Furthermore, the Nrf2 impairment mirrored at the systemic level in PBMCs of patients may help to open new perspectives for biomarker research in FA, potentially useful for monitoring clinical trials.

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV-1 vector

Maria Ventosa, Zetang Wu and Filip Lim; The Journal of Gene Medicine, Accepted manuscript online: 17 OCT 2017 08:40PM EST DOI: 10.1002/jgm.2993

With the aim of developing a gene therapy for FA neuropathology, here we describe the construction and preliminary characterization of a high capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B-FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1.

We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglion neurons with the H24B-FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B-FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month.

Our results support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy.

BioMarin Selects BMN 290 for Friedreich's Ataxia

SAN RAFAEL, Calif., Oct. 18, 2017 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) updated the investment community on the Company's development portfolio, which is focused on innovative therapies to treat rare and ultra-rare diseases.
BioMarin announced today that it has selected BMN 290, a selective chromatin modulation therapy, for the treatment of Friedreich's Ataxia (FA). FA is a rare autosomal recessive disorder with worldwide prevalence of approximately 15,000, which results in disabling neurologic and cardiac progressive decline. Currently there are no approved disease modifying therapies for FA. In preclinical models, BMN 290 increases frataxin expression in affected tissues more than two-fold. BMN 290 is a second generation compound derived from a compound acquired from Repligen that had human clinical data demonstrating increases in frataxin in FA patients. BMN 290 was selected for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. The company expects to submit the IND in 2H 2018.

New data for Friedreich's ataxia with a novel capsid demonstrate reversal of disease phenotype in a preclinical disease model.

Press Release: CAMBRIDGE, Mass., Oct. 17, 2017 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases announced today multiple data presentations at the Congress of the European Society of Gene and Cell Therapy (ESGCT) taking place October 17-20, 2017, in Berlin, Germany. The data include an oral presentation related to recent results from Voyager's ongoing Phase 1b trial of VY-AADC01 in advanced Parkinson's disease, as well as six poster presentations related to Voyager's novel adeno-associated virus (AAV) capsid optimization efforts, gene therapy manufacturing, and preclinical pipeline programs.

Rescue of Central and Peripheral Neurological Phenotype in a Novel Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin." Poster P107.

Friedreich's ataxia is a severe, inherited neurological disease caused by mutations in the frataxin gene leading to decreased expression of frataxin (FXN), which results in severe sensory impairment, progressive loss of the ability to walk, generalized weakness, loss of sensation, as well as severe and potentially fatal cardiomyopathy. In a transgenic mouse model of FA, one-time intravenous post-symptomatic dosing of an AAV vector composed of a novel AAV capsid and a frataxin transgene, together with intracerebral dosing also delivering a frataxin transgene, rapidly halted and reduced FA disease progression in multiple tests including three functional tests of motor behavior and one electrophysiological test. In addition, increasing intravenous vector doses with the same novel capsid together with a fixed dose of the intracerebral vector led to a dose-dependent rescue of the FA phenotype. This novel AAV capsid provided at least 20-fold greater delivery of the vector to sensory ganglia as measured by vector genomes, and approximately a three-fold greater expression of frataxin in the cerebellum, as compared to an AAV9 vector at a similar dose. Additional preclinical studies are underway at Voyager including steps to optimize a lead clinical candidate for the treatment of FA.

New data for Friedreich's ataxia with a novel capsid demonstrate reversal of disease phenotype in a preclinical disease model.

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:
•
•Children's Hospital of Philadelphia, David Lynch, Prospective study in Friedreich's ataxia, approximately $2 million over 5 years
•

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.