FACTs Fabry gene therapy clinical trial: Two-year data

Fabry disease is due to a deficiency in alpha-galactosidase A (a-gal A) activity. Enzyme therapy is used to treat Fabry disease although the cost is high and biweekly infusions are required long-term. We have shown that when a-gal A is overexpressed in cells, a portion of the hydrolase is secreted and can be taken up and used functionally by unmodified bystander cells. Based on this concept, and building on extensive preclinical data we generated previously, we have launched a multi-center, phase I clinical trial in Canada using gene transfer to treat men with Fabry disease of the classical phenotype (clinicaltrials.gov#NCT02800070) and to determine the feasibility and safety of this procedure. The protocol involves mobilization of Fabry patient hematopoietic stem/progenitor cells (HSPCs), ex vivo recombinant lentivirus-mediated gene transfer of a codon-optimized human a-gal A cDNA into those cells, and infusion of the transduced HSPCs into minimally ablated autologous recipients. The first Fabry patient received a single dose of vector-transduced cells in January 2017. Since then two other Fabry patients have also received the transduced cell product (with more patients in the queue). With regards to safety - no serious adverse events have occurred in any Fabry patient in our trial to date. We now report results for patient 1 at two years post-infusion of the transduced cells. We tracked a-gal A activity in leukocytes and plasma, vector copy number in peripheral blood and bone marrow cells, antibody titers in plasma, and changes to enzyme substrates and catabolites in both plasma and urine. Results show durable engraftment and persistence of vector-transduced HSPCs in this Fabry patient that are functionally enabled to produce a-gal A continually. This protocol appears to be feasible and safe however, application to other patients and long-term effectiveness are still to be studied