Testing of optimized gene therapy vector shows positive results in Sanfilippo type B mice

September 12, 2022

Newly-published research, led by Professor Coy Heldermon at the University of Florida, has described the use of an optimized gene therapy vector to treat a mouse model of Sanfilippo Syndrome Type B.

Researchers used an AAV8 viral delivery vector that they had optimized in a previous study, called AAVtcm8-coNAGLU, to deliver Naglu, the gene that is affected in Sanfilippo Type B. The ‘shell’ of this delivery virus has three introduced changes that were found to enhance the production of the enzyme from the gene and its distribution in the brain. It is hoped that the new virus will produce a more efficient gene therapy compared to prior technology.

In the new study, three- or four-day-old mice with Sanfilippo Type B were injected with the gene therapy via one of two routes of administration: a single intracisternal injection (into fluid-filled spaces at the base of the brain) or six intraparenchymal injections (into the brain tissue itself). Irrespective of the injection method, the treatment was well-tolerated, with no adverse effects seen in the mice.

To test the effectiveness of the optimized gene therapy vector in mice, the team measured disease indicators including NAGLU enzyme activity, heparan sulfate levels, and the mice’s sleep cycle, hearing, and lifespan.

At six months of age, Sanfilippo Type B mice treated with gene therapy via both injection methods had NAGLU activity in the brain significantly higher than normal levels. By around 21 months of age, NAGLU activity in the brain remained above normal levels.

The team found that heparan sulfate, the complex sugar that builds up in the disease, was significantly reduced in the treatment groups. All mice that received the gene therapy showed normal heparan sulfate levels at six months of age.

When activity levels of the treated mice were measured at five months of age, they were found to be similar to normal, indicating an improvement in the sleep cycle post-therapy. Hearing loss is common in Sanfilippo syndrome and also occurs in the mouse model of Sanfilippo Type B. Encouragingly, the team saw improvements in hearing in the mice treated with the gene therapy, particularly via the single intracisternal injection method. Mice that received the gene therapy in the study also survived to at least twice the age of untreated mice.

The results of this study suggest that this optimized gene therapy vector, and its delivery via either route tested, could be a potential therapeutic candidate for patients with Sanfilippo Type B. The team note the need for additional studies before regulatory approval for a clinical trial could be sought, including the treatment of older mice to determine the effective treatment window.

This study was partly funded by the Sanfilippo Children’s Foundation (Australia), Fundacja Sanfilippo (Poland), Sanfilippo Initiative (Germany), and Cure Sanfilippo Foundation (USA).

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