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

Inclusion Criteria:

Males and females, age 18 to 50
Willing and able to provide informed consent
Definitive diagnosis of FA, based on clinical phenotype and genotype (GAA expansion on 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 be abnormal in ≥2 of the following parameters, at least one of which is an abnormal cardiac MRI left ventricular mass index or abnormal cardiopulmonary exercise test

In the absence of other factors known to cause left ventricular hypertrophy, cardiac MRI left ventricular mass index >2 standard deviations above the normal range (males >84 gm/m2, females >69 gm/m2)
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 insure consistency of effort, peak RER ≥1.0
Cardiac MRI stroke volume index <45 mL/m2
Cardiac MRI global longitudinal left ventricular strain <20%
Serum high-sensitivity cardiac troponin above the normal range
Fibrosis ≤10% in the left ventricular wall on late gadolinium enhancement cardiac MRI
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 liver ultrasound and serum alpha fetoprotein
Normal kidney function as assessed by plasma urea and creatinine; estimated GFR >30 mL/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 prevent pregnancy for the duration of the study
Individuals not receiving experimental medications or participating in another experimental protocol for at least 12 wk prior to entry to the study (individuals who 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 >38.5̊ C, infiltrate on chest x-ray
Decompensated heart failure (NY4A class III-IV at time of baseline clinical assessment)
Hemoglobin <10 g/dl
Absolute neutrophil count <1500 cells/mm3
Platelet count <100,000 cells/mm3
Hemodynamically unstable atrial or ventricular arrhythmias which require medical intervention
Contraindication to cardiac MRI (e.g., non-MRI compatible pacemaker/defibrillator) or gadolinium (known or suspected hypersensitivity, glomerular filtration rate <30 mL/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 ventricular hypertrophy, including aortic stenosis, systemic hypertension (BP ≥140/90 on noninvasive blood pressure), or genetically mediated hypertrophic cardiomyopathy
Use of oxygen supplementation
Risk for thromboembolic disease, including history of thromboembolic disease hospitalization within the last 90 days, recent trauma and/or recent surgical procedure. If the history of thromboembolic disease is not definitive, the subject will be excluded if laboratory testing suggests a risk for thromboembolic disease because of mutations in the protein-S, protein C, antithrombin, factor V Leiden or prothrombin 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 of myocardial infarction, prior coronary revascularization or angina symptoms (Canadian Cardiovascular Society grade ≥2 at time of baseline clinical assessment), or epicardial obstructive coronary artery disease (≥ 50% left main, ≥ 70% of other major coronary arteries)
Any lung function abnormalities that would affect cardiopulmonary testing
Any condition, disorder, or abnormal laboratory test findings at screening which, in the judgment of the investigator, would interfere with the individual's ability to comply with all study requirements, or would require the administration of treatment during 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 in the study
If prior infection with SARS-CoV2, any related residual cardiac or pulmonary abnormalities
Alcoholism or drug addiction (see reference 71 for alcoholism, reference 72 for drug addiction)