AVR-RD-03, Avrobio’s investigational blood stem cell gene therapy for classic childhood Pompe disease, has been shown to be safe and effective in a mouse model of the disease.

The results, presented as a poster at the 2022 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting in Washington, DC, demonstrated that at eight months after treatment with AVR-RD-03, toxic glycogen accumulation was reduced to healthy levels in several tissues.

The preclinical data supports the company’s plans to move into a clinical trial next year, according to Avrobio.

“We believe there is an urgent need for new treatment options that can address the systemic impact of Pompe disease and our preclinical data suggests that a dose of [blood stem cell gene therapy]can potentially normalize glycogen levels in key tissues and potentially halt or potentially reverse the impact of head-to-toe Pompe disease,” said Essra Ridha, MD, Avrobio’s chief medical officer, in a press release. .

Classic infantile pump is a rare lysosomal storage disease caused by inefficient production or function of an enzyme called acid alpha-glucosidase (GAA). This leads to the buildup of glycogen, a sugar molecule, in lysosomes (small recycling structures in cells) in muscles and in the central nervous system – the brain and spinal cord.

Symptoms of classic infantile Pompe disease, which appear soon after birth, include muscle weakness, delayed motor development, heart problems and difficulty breathing.

Avrobio’s AVR-RD-03 uses a glycosylation-independent lysosomal targeting (GILT) tag licensed from BioMarin to enhance the delivery of GAA lysosome gene. The GILT tag should improve the delivery of treatment to target tissues.

The experimental therapy is delivered in a modified lentivirus vector, which is then delivered to blood stem cells. In this way, the genetic sequence is incorporated into the DNA of the stem cell. Once the modified stem cells are transplanted into mice, they can differentiate in the bone marrow into blood cells that produce the working version of the GAA enzyme. These modified cells can eventually reach all the tissues of the body through the blood.

Results of a study with six gene therapy groups in mice showed that stem cell transplantation was stable for up to eight months after a single infusion of AVR-RD-03.

After eight months, significant GAA enzyme activity was measured in the bone marrow, ranging from a median of 300 to 534 nanomoles/h/mg, compared to approximately 4 to 6 nmoles/h/mg in normal mice.

As previously reported, glycogen accumulation was reduced by more than 99% in the heart and heart muscle thickening was also reversed. Glycogen levels were reduced by more than 95% in the brain, 99% in the spinal cord, 97% in the diaphragm (a domed muscle important for breathing), and 85% in the quadriceps ( thigh). Motor function was also significantly improved seven months after treatment.

According to the company, the results show that the type of vector used to deliver the gene to blood stem cells is safe. Avrobio also revealed that in a separate study, researchers were able to effectively replace the missing gene and produce an active enzyme in human blood stem cells using the modified lentivirus.

“These data show substantial substrate reduction in key tissues, muscle and CNS, reduced tissue pathology and correction at the functional level, all of which are highly relevant for potential future translation in Pompe patients,” Niek P van Til, PhD, research leader and consultant for Avrobio, said.