Next-gen Sanfilippo Type A Gene Therapy May Move Into Clinical Trial

Following the promising results of a second-generation gene therapy in a mouse model of Sanfilippo syndrome type A, a first trial in patients might be launched this year.

If further work on this gene therapy continues to show potential, “there is hope to start a trial in 2021,” the Sanfilippo Children’s Foundation stated in a news story reporting about the research.

Gene therapies are currently at the forefront of research for diseases with a genetic cause, including Sanfilippo syndrome type A, also known as mucopolysaccharidosis type IIIA (MPS IIIA).

The disease is due to mutations in the SGSH gene that lead to a lack of the enzyme sulfamidase. The result is a toxic accumulation of large sugar molecules — called glycosaminoglycans (GAGs) — such as heparan sulfate within cells and tissues.

Gene therapies target the root of the disease, as they are designed to deliver a working copy of the SGSH gene to increase or restore sulfamidase activity levels and so reduce or prevent GAG and heparan sulfate accumulation.

Gene therapies currently being developed for Sanfilippo type A use adeno-associated viruses (AAV), which are modified in the lab to not cause disease, as gene therapy delivery vehicles. Some therapies are administered directly into the bloodstream, while others are injected into the brain.

A potentially improved second-generation gene therapy, developed by researchers at the University of North Carolina School of Medicine and its Gene Therapy Center, uses a self-complementary AAV type 9 (scAAV9). It was named scAAV9-hSGSH.

This new version is, in principle, more effective since it requires fewer steps from the delivery of the SGSH gene to its target cells — located in the central nervous system (CNS, brain and spinal cord) and peripheral organs — to the production of a working version of its protein.

The researchers previously tested three escalating doses of the gene therapy — 2.5×10¹², 5×10¹², and 1×10¹³ vector genomes/kg or  vg/kg — given directly into the bloodstream of mice in a disease model at three different ages (1, 3, and 6 months old).

Results showed that a single administration, regardless of the dose used, was sufficient to rapidly increase sulfamidase activity levels in all evaluated tissues, including peripheral organs and the brain. A significant drop in GAG accumulation across the tested tissues, to levels similar to those seen in healthy mice, was reported.

Most importantly, these effects were accompanied by a rescue to normal levels in cognitive and motor functions, as well as better survival. Treated older mice, despite taking longer to respond than younger mice, also lived as long as a control mouse group without the disease.

According to the press release, the new gene therapy also induced its beneficial effects at lower doses than those used in earlier gene therapies for Sanfilippo type A.

No adverse side effects or treatment-related tissue abnormalities were detected, supporting the gene therapy’s safety profile.

Funding from the Abby Grace Foundation and Aislinne’s Wish Foundation supported the preclinical animal work, and further support by Abby Grace and the Cure Sanfilippo Foundation will allow researchers to continue their studies.