Benzinga | Feb 8, 2021 02:31PM EST

Amicus Therapeutics Highlights Presentation Of Preclinical Fabry Disease Gene Therapy Data At 17th Annual WORLDSymposium 2021

Amicus Therapeutics (NASDAQ:FOLD) today announced initial preclinical data from its investigational adeno-associated viral (AAV) gene therapy program for Fabry disease in mice. The results are featured in a virtual poster presentation at the 17th Annual WORLDSymposium(tm) 2021, being held February 8-12, 2021. The poster is also available in the Events and Presentations section of the Amicus Therapeutics corporate website.

Fabry disease is an inherited lysosomal disorder caused by deficiency of the enzyme alpha-galactosidase A (GLA). Reduced or absent levels of GLA lead to accumulation of disease substrate leading to cellular disfunction and organ damage, which results in the clinical manifestations of Fabry disease. Amicus, in collaboration with the Gene Therapy Program of the Perelman School of Medicine at the University of Pennsylvania (Penn), is developing a novel gene therapy for Fabry disease that combines the Amicus protein-engineering expertise and deep knowledge and experience in Fabry disease with Penn's adeno associated virus (AAV) gene transfer technologies.

This initial preclinical study assessed a range of single doses of AAV in Gla knockout (KO) mice with either natural unmodified hGLA ("wildtype hGLA") or Amicus/Penn engineered hGLA transgenes ("engineered hGLA"). The Amicus/Penn engineered hGLAs are designed for improved stability which is believed to provide a larger window for the enzyme to stay active while in circulation prior to being taken up into the target tissues and for additional stabilization after cell uptake. The lead Amicus/Penn engineered hGLA declared as an IND candidate is designated as AT-GTX-701.

Preclinical Poster Highlights for Amicus/Penn AAV Gene Therapy for Fabry Disease:

* Improved for stability: In vitro characterization of two stabilized alpha-Gal A constructs with engineered disulfide bonds demonstrated stable homodimer formation, enhanced temperature, plasma, and neutral pH stability compared to wildtype.

* Dose dependent response: The lowest tested dose of AT-GTX-701 in Gla KO mice showed partial substrate reduction, while highest tested dose resulted in near complete substrate reduction.

* Significantly greater substrate reduction vs. wildtype transgene: AT-GTX-701 demonstrated significantly greater lyso-Gb3/GL-3 substrate reduction across all Fabry disease relevant tissues including the dorsal root ganglia (DRG), kidney, and heart, with reductions at low dose being equal to or greater than the reductions observed at higher doses with wildtype transgene.

* First evidence of dorsal route ganglia storage reduction: DRG are affected in Fabry disease and associated with neuropathic pain. AT-GTX-701's stabilized transgene provided the first evidence for DRG storage reduction in a Fabry mouse model treated with an AAV gene therapy.

* Amicus/Penn Gene Therapy Platform: Further validates the potential of this platform to design constructs that enhance proteins across multiple lysosomal disorders.

* Additional preclinical studies, IND enabling studies, and GMP manufacturing process development are underway.

Hung Do, Ph.D., Chief Science Officer of Amicus Therapeutics, stated, "These very important preclinical results validate our capabilities to develop engineered proteins via a gene therapy that can result in superior substrate reduction compared with a wildtype transgene. This is the second program in our collaboration with Penn that has demonstrated the potential advantages of optimizing the target protein in these disorders, and may be applicable to other lysosomal disorders as we continue to combine our understanding of the molecular basis of these diseases and expertise in protein engineering, together with Penn's vector engineering expertise, to develop novel gene therapies."

Amicus is currently developing AAV gene therapies in collaboration with Penn for Pompe disease, Fabry disease, CDD, CLN1, MPS IIIB, a next generation program in MPS IIIA, as well as Angelman Syndrome. The agreement between Amicus and Penn is a Research, Collaboration and License Agreement, providing funding to Penn to advance the preclinical research programs in the Wilson Lab and to license certain technologies invented under the funded Research Collaboration.