AVR-RD-03 Gene Therapy Reduces Toxic Glycogen Buildup in Pompe Mouse Model

AVR-RD-03, Avrobio‘s investigational gene therapy for classic infantile-onset Pompe disease, was found to reduce toxic glycogen accumulations to healthy levels in a mouse model of Pompe.

These results, presented during an Avrobio Virtual R&D Day webcast on Nov. 17, suggest AVR-RD-03 has potential as a part of the company’s portfolio of gene therapy candidates.

“We believe that all six of our pipeline programs share tremendous synergies in clinical development, manufacturing, regulatory processes and commercialization. This second wave of programs will evaluate our promising investigational therapies in diseases with high unmet medical need for patients and families,” Chris Mason, MD, PhD, chief scientific officer of Avrobio, said in a press release.

“We believe the opportunity we have to potentially prevent patients, especially children, from developing the disabilities that would otherwise result from their inherited genetic code — to perhaps give them the possibility of a full and healthy life — is humbling,” Mason added.

Classic infantile-onset Pompe, a disease type with a poor response to enzyme replacement therapy, is caused by a deficiency in the enzyme acid alpha-glucosidase (GAA). This results in the accumulation of the sugar molecule glycogen in lysosomes — structures that break down substances in the cell — of cardiac and other muscles, as well as in the central nervous system (brain and spinal cord).

AVR-RD-03, a gene therapy intended for all Pompe patients, uses a Glycosylation-Independent Lysosomal Targeting (GILT) tag licensed from BioMarin to enhance the targeted delivery of the GAA gene to lysosomes. The treatment is delivered in a modified lentivirus vector.

A mouse model of classic infantile-onset Pompe disease was treated with a one-time infusion of AVR-RD-03. Results showed that, at nearly four months post-treatment, AVR-RD-03 induced GAA production, and reduced glycogen accumulation by more than 99% in the cardiac muscle. Structure alterations in the heart also were reversed.

At eight months post-infusion, the glycogen levels had been reduced by over 95% in the brain, 99% in the spinal cord, 97% in the diaphragm, and 85% in skeletal muscles. In fact, glycogen levels in mice treated with AVR-RD-03 were nearly indistinguishable from healthy mice, the company said.

According to Avrobio, the GILT tag promotes delivery to multiple hard-to-reach tissues, thereby increasing the effectiveness of the therapy. The company is exploring options to rapidly advance AVR-RD-03 into clinical trials, pending approval from the U.S. Food and Drug Administration.

During the webcast, Avrobio also announced the addition of Gaucher disease type 3 to its gene therapy program, which along with Hunter syndrome and Pompe disease, are part of the company’s second wave of treatments focused on lysosomal storage disorders. Overall, the program aims to ease the patient burden of currently available enzyme replacement therapies, which require multiple infusions.

By the end of 2021, AVROBIO aims to have dosed 30 patients across multiple trials including the second wave pipeline.