Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia

Inclusion Criteria:

• Males and females, age 12 to 50

• Willing and able to provide informed consent

• Definitive diagnosis of FA, based on clinical phenotype and genotype (GAA expansionon both alleles)

• >600 GAA repeats in intron 1 in at least one allele

• FARS and SARA neurologic scores consistent with diagnosis of Friedreich's ataxia

• Left ventricle ejection fraction (EF) measured by cardiac MRI of ≥35% to 75%

• Evidence of FA-related cardiac disease, must meet the following criteria: must beabnormal in ≥2 of the following parameters, at least one of which is an abnormalcardiac MRI left ventricular mass index or abnormal cardiopulmonary exercise test

1. Adults: In the absence of other factors known to cause left ventricularhypertrophy, cardiac MRI left ventricular mass index >2 standard deviationsabove the normal range (males >84 gm/m2, females >69 gm/m2 or Pediatrics: Inthe absence of other factors known to cause left ventricular hypertrophy,cardiac MRI left ventricular mass index >95th centile based on normal BSA fortheir age and gender

2. Cardiopulmonary arm crank testing with assessment of VO2 max ≤20 mL/kg-min,peak VO2 ≥10 mL/kg-min while maintaining revolutions of ≥40/min. To insureconsistency of effort, peak RER ≥1.0

3. Cardiac MRI stroke volume index <45 mL/m2

4. Cardiac MRI global longitudinal left ventricular strain <20%

5. Serum high-sensitivity cardiac troponin above the normal range

• Fibrosis ≤10% in the left ventricular wall on late gadolinium enhancement cardiacMRI

• Resting O2 saturation ≥95%

• Serum neutralizing anti-AAVrh.10 titer <1:125

• Hematocrit >30%

• White blood cell levels within normal limits

• Normal prothrombin, partial thromboplastin time

• Normal liver-related serum parameters (ALT, AST, ALP, bilirubin); normal liverultrasound and serum alpha fetoprotein

• Normal kidney function as assessed by plasma urea and creatinine; estimated GFR >30mL/min/1.73m2

• No evidence of active infection of any types, including hepatitis virus (A, B or C),human immunodeficiency virus (HIV-1 and HIV-2), or SARS-CoV2

• Fertile individuals should utilize barrier birth control measures to preventpregnancy for up to 6 months after vector administration

• Individuals not receiving experimental medications or participating in anotherexperimental protocol for at least 12 wk prior to entry to the study (individualswho are/have received approved therapy will be included).

• Capable of undergoing cardiac MRI

• No contraindications to receiving corticosteroid immunosuppression

Exclusion Criteria:

• Individuals receiving corticosteroids or other immunosuppressive medications

• Individuals with uncontrolled diabetes (glycated hemoglobin, HbA1c levels >7%)

• Genotype FA missense mutation on one or both alleles

• Evidence of infection defined by elevated white blood cell count, temperature >38.5̊C, infiltrate on chest x-ray

• Decompensated heart failure (NY4A class III-IV at time of baseline clinicalassessment)

• Hemoglobin <10 g/dl

• Absolute neutrophil count <1500 cells/mm3

• Platelet count <100,000 cells/mm3

• Hemodynamically unstable atrial or ventricular arrhythmias which require medicalintervention

• Contraindication to cardiac MRI (e.g., non-MRI compatible pacemaker/defibrillator)or gadolinium (known or suspected hypersensitivity, glomerular filtration rate <30mL/min/1.73m2)

• Any malignancy during the last five years, except basal cell skin cancer

• Unrelated clinical condition with life expectancy <12 months (prohibiting follow-up)

• Concomitant conditions (other than FA) known to produce left ventricularhypertrophy, including aortic stenosis, systemic hypertension (BP ≥140/90 onnoninvasive blood pressure), or genetically mediated hypertrophic cardiomyopathy

• Use of oxygen supplementation

• Risk for thromboembolic disease, including history of thromboembolic diseasehospitalization within the last 90 days, recent trauma and/or recent surgicalprocedure. If the history of thromboembolic disease is not definitive, the subjectwill be excluded if laboratory testing suggests a risk for thromboembolic diseasebecause of mutations in the protein-S, protein C, antithrombin, factor V Leiden orprothrombin gene

• Any uncontrolled psychiatric disease

• Pregnant or breastfeeding woman

• Prior participation in any gene and/or cell therapy

• Known obstructive coronary artery disease (as documented by clinical history ofmyocardial infarction, prior coronary revascularization or angina symptoms (CanadianCardiovascular Society grade ≥2 at time of baseline clinical assessment), orepicardial obstructive coronary artery disease (≥ 50% left main, ≥ 70% of othermajor coronary arteries)

• Any lung function abnormalities that would affect cardiopulmonary testing

• Any condition, disorder, or abnormal laboratory test findings at screening which, inthe judgment of the investigator, would interfere with the individual's ability tocomply with all study requirements, or would require the administration of treatmentduring the study that could potentially affect the interpretation of the study data,or would place the individual at an unacceptable risk by his/her participation inthe study

• If prior infection with SARS-CoV2, any related residual cardiac or pulmonaryabnormalities

• Alcoholism or drug addiction (see reference 71 for alcoholism, reference 72 for drugaddiction)