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Kidney Week

Abstract: PO1623

AVR-RD-01, an Investigational Lentiviral Gene Therapy for Fabry Disease, Reduces Gb3 Substrate in Endothelial Cells of Renal Peritubular Capillaries

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Thomas, Mark AB, Royal Perth Hospital, Perth, Western Australia, Australia
  • Trame, Mirjam, AVROBIO, Cambridge, Massachusetts, United States
  • Mason, Chris, AVROBIO, Cambridge, Massachusetts, United States
  • Volck, Birgitte, AVROBIO, Cambridge, Massachusetts, United States

Lysosomal disorders are attractive candidates for ex vivo gene therapy based on the potential to transform a patient’s own cells into a drug product to deliver sustained functional protein/enzyme after a single treatment. Fabry disease (FD) is caused by mutations in the GLA gene that result in functional deficiency of the lysosomal enzyme, alpha-galactosidase A (AGA), which leads to pathological accumulation of substrates and metabolites, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Significant morbidity and early mortality result from damage to kidneys, heart, and brain.


AVR-RD-01 is an investigational ex vivo gene therapy that involves transplantation of autologous stem cells genetically modified with a lentiviral vector which inserts into the human genome a complementary deoxyribonucleic acid (cDNA) sequence that encodes for functional human AGA.


In a Phase 1 trial of AVR-RD-01, 5 patients, previously on enzyme replacement therapy (ERT), after gene therapy demonstrated increases in plasma and leukocyte AGA activity and decreases in substrate (Gb3) and metabolite (lyso-Gb3) in plasma, now sustained up to 32 months. A Phase 2 clinical trial in 8-12 treatment-naïve males (16-50 years) with classic FD investigates the safety, tolerability, and efficacy of AVR-RD-01, including its effect on substrate accumulation in the kidney after 48 weeks.

Kidney biopsy results for the first patient in the Phase 2 clinical trial demonstrated reduction in renal peritubular capillary (PTC) Gb3 inclusions, quantitatively assessed by the BLISS methodology. At 48 weeks, Gb3 inclusions were reduced from an average of 3.55 to 0.47 per PTC corresponding to an 87% reduction versus baseline (BL). Leukocyte and plasma AGA activity increased, associated with declines in plasma and urine Gb3 and lyso-Gb3, including an 87% reduction in plasma lyso-Gb3 at 48 weeks versus BL. Adverse events were as expected with the particular conditioning regimens (i.e. mild/moderate and quickly resolving), underlying FD and pre-existing conditions, with no serious adverse events related to AVR-RD-01 drug product. Low-titer anti-AGA antibodies were transiently detected at week 24.


The latest results from this ongoing open label Phase 2 study will be shared.


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