Gene therapy for heart issues in Friedreich's ataxia

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

This study is testing a new gene therapy for heart problems in people with Friedreich's ataxia to see if it is safe and helps improve their heart function.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 12 Years to 50 Years
• Sex: All
• Sponsor: Weill Medical College of Cornell University (other)
• Locations: 1 site (New York, New York)
• Trial ID: NCT05302271 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the safety and initial effectiveness of AAVrh.10hFXN, a gene therapy designed to treat cardiomyopathy associated with Friedreich's ataxia. Participants will receive the therapy intravenously in a phase 1, open-label, dose escalation format involving 25 individuals. The study focuses on patients with specific genetic markers and cardiac conditions related to Friedreich's ataxia, assessing their heart function through various tests.

Who should consider this trial

Good fit: Ideal candidates are males and females aged 18 to 50 with a definitive diagnosis of Friedreich's ataxia and evidence of related cardiac disease.

Not a fit: Patients outside the age range or without a confirmed diagnosis of Friedreich's ataxia may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could improve heart function and overall health for patients with Friedreich's ataxia.

How similar studies have performed: Other studies using gene therapy for similar conditions have shown promise, indicating potential for success in this approach.

Eligibility criteria

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, 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

  1. 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 or 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
  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 insure consistency 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 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)

Where this trial is running

New York, New York

• Weill Cornell Medicine — New York, New York, United States (RECRUITING)

Study contacts

• Principal investigator: Ronald G Crystal, MD — Weill Medical College of Cornell University
• Study coordinator: Maddie Galbraith, BS

Conditions: Friedreich Ataxia, Cardiomyopathies, Cardiac Hypertrophy, Myocardial Fibrosis, Ataxia, Friedreich's ataxia, Pediatric, Gene therapy