Autologous Stem Cell Transplantation of Cells Engineered to Express Alpha-Galactosidase A in Patients With Fabry Disease

Inclusion criteria

• Male patients 18-50 years of age at the time of enrollment
• Diagnosis of Fabry disease (FD) as defined by very low or absent α-gal A activity
• Classic FD Type I phenotype with alpha-galactosidase A (GLA) genotyping
• Patients on enzyme replacement therapy (ERT) prior to enrollment
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1
• Adequate organ function within 21 days prior to Pre-Treatment Phase:
• Willing and capable of signing and giving written informed consent in accordance with Research Ethics Board (REB) requirements
• Willing to comply with all procedures outlined in the study protocol, cooperative with the protocol schedule, able to return for safety evaluation, or otherwise likely to complete the study
• Willing to abstain from sexual activity or willing to use condoms during sexual intercourse from day of Melphalan administration on day -1 of Phase 3 until after 12 months follow-up post-transplant.
• Willing to not donate sperm after receiving Melphalan. Sperm banking will be recommended to any patient who would like to father children in the future.

Exclusion criteria

• Males with variant Fabry Disease.
• Female gender
• Use of immunosuppressive agents or any anticoagulant
• Ongoing ERT-related infusion associated reactions of moderate-to-severe intensity
• Presence of anti-agalsidase immunoglobulin (Ig)G antibodies above a threshold (5-fold above normal;) or evidence of high titre neutralizing antibodies
• Blood test positive for Hepatitis B virus (HBV), Hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (HTLV-1), human T-cell lymphotropic virus type 1 (HTLV-2), or Venereal Disease Research Laboratory test (VDRL; Transmissible Disease (TD) testing will be done in Pre-Treatment Phase 2 - see section 5.1 for full panel of TD tests. Patients will only be excluded from the study if positive for the TD tests listed here in this exclusion).
• Uncontrolled bacterial, viral, or fungal infections
• Prior malignancies except resected basal cell carcinoma
• Chronic Kidney Disease (CKD) stage >2
• History of heart failure or left ventricle ejection fraction (LVEF) <45% or moderate to severe diastolic dysfunction by standard criteria
• Arrhythmia: bundle branch block, heart block degree II or III, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, cardiac arrest, pacemaker, implantable cardiac defibrillator
• Coronary artery disease with angina, prior myocardial infarction, percutaneous transluminal coronary angioplasty with or without stent, coronary artery bypass graft surgery, moderate to severe valvular heart disease, valve replacement surgery
• Uncontrolled hypertension
• Diabetes mellitus
• Advanced liver disease, liver failure, cirrhosis
• Immune deficiency state
• Moderate-to-severe chronic obstructive pulmonary disease (COPD)
• Any hematological condition with white blood cells (WBC) <3.0 x109/L, platelet count <100 x109/L, and/or hemoglobin <100 g/L
• Prior bone marrow transplant (BMT) or organ transplant
• Any condition that would preclude use of Melphalan
• Use of a drug with cytotoxic or immunosuppressive effect within 60 days of trial entry
• Uncontrolled psychiatric disorder
• Active chronic infection
• Prior tuberculosis
• Any other serious concurrent disease
• Cognitive impairment that would prevent informed consent
• Use of an investigational drug within 30 days of stem cell transplant (SCT)