Estudio de fase IA de la terapia génica AAVrh.10hFXN para la miocardiopatía de la ataxia de Friedreich

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 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 that falls into one of the 2 categories: Early disease (defined by serum high sensitivity troponin above the normal range, without increased LVMI) or Advanced disease (defined as high sensitivity troponin above the normal range and increased LVMI).

  • Increased LVMI in adults: 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)
  • Increased LVMI in pediatrics: In the absence of other factors known to cause left ventricular hypertrophy, cardiac MRI left ventricular mass index >95ᵗʰ centile based on normal BSA for their age and gender

• 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

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)