Abstract. The goal of this R61/R33 proposal is to carry out a phase IA/IB clinical study of
AAVrh.10hFXN (a serotype rh.10 adeno-associated virus coding for human frataxin) to treat
cardiac manifestations of Friedreich’s ataxia (FA), the most common inherited ataxia. FA is a fatal,
presently, untreatable disorder. Most cases result from intron variants in the frataxin (FXN) gene; when
inherited from both parents, there is resulting haploinsufficiency of FXN gene expression. While
progressive neurologic disease limits mobility, cardiomyopathy is responsible for substantial morbidity and
60% of deaths secondary to progressive heart failure and arrhythmias. Cardiac MRI (CMR) data from our
group and others demonstrate that FA-associated cardiomyopathy initially manifests with increased left
ventricular (LV) myocardial mass (a potentially reversible phenotype) prior to development of myocardial
fibrosis (irreversible damage). AAVrh.10hFXN, the therapeutic gene transfer vector to be used in the
proposed human study, is a nonhuman primate-derived serotype rh.10 capsid with a constitutive promoter
driving the normal human frataxin cDNA. AAVrh.10hFXN will be administered intravenously, a vector and
route which in experimental animal models effectively delivers genes to the heart. Based on our preclinical
efficacy data in two murine models in which intravenous AAVrh.10hFXN reverses the consequences of FA
cardiomyopathy, together with extensive safety data, we are ready to initiate a phase IA/IB clinical trial
with the following aims. R61 aim 1. Prepare and submit an Investigational New Drug package and gain
approval from the FDA and other regulatory groups (Institutional Review Board, Biosafety) to initiate a
phase IA/IB clinical trial. Milestone. Full regulatory approval to initiate parts A and B of the clinical trial,
enroll the 1st subject in part A. R61 aim 2 and milestone. Manufacture clinical grade AAVrh.10hFXN for
the part A (safety/dose-ranging) clinical trial. R33 aim 3. Carry out the part A (safety/dose-ranging) trial to
determine the maximum tolerable dose of AAVrh.10hFXN therapy for the cardiac manifestations of FA.
Milestone. Initiate and complete assessment of n=9 individuals (3 doses, 3 each), with an audited final
report. R33 aim 4 and milestone. Manufacture clinical grade AAVrh.10hFXN for part B (safety/preliminary
efficacy) clinical trial. R33 aim 5. Carry out the part B safety/preliminary efficacy study at the highest
tolerable dose from part A. Milestone. Complete assessment of n=15 individuals, with an audited final
report. Given that genetic variance is responsible for many forms of cardiomyopathy and that existing
treatments are limited, this study offers a potential therapeutic paradigm shift to reverse cardiac phenotype
and thus improve clinical outcomes for a broad range of patients with genetically mediated
cardiomyopathies at risk adverse LV remodeling and its devastating clinical consequences.