Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia
The purpose of this study is to test the safety and preliminary efficacy of AAVrh.10hFXN to treat the cardiomyopathy associated with Friedreich's ataxia (FA). AAVrh.10hFXN is a serotype rh.10 adeno-associated virus gene transfer vector coding for Frataxin (FXN). The drug is administered intravenously. This is a phase 1, open label, dose escalation study with a total of 25 participants.
• 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 up to 6 months after vector administration
• 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