Researchers at The University of North Carolina have developed a second-generation gene therapy for Sanfilippo, with preclinical tests performed in a Sanfilippo type A mouse model. Further work on this gene therapy project will be funded by the Abby Grace Foundation in collaboration with Cure Sanfilippo Foundation, both located in the US, with the hope that a clinical trial is on the horizon.
Sanfilippo Syndrome is a genetic condition that causes a deficiency in an enzyme required to break down the complex sugar, heparan sulphate (HS). This results in the accumulation of HS with devastating effects seen particularly in the brain. As one of four subtypes, Sanfilippo type A involves the gene SGSH and its enzyme product called sulfamidase.
While there are currently no approved treatments for Sanfilippo, many potential treatments are under active investigation in both the laboratory and clinical trials. Gene therapy is one avenue at the forefront of this research. Its strength lies in its ability to treat the root cause of the disease by delivering a healthy copy of the gene into the body, which is used to make the functional enzyme to break down HS.
In the Sanfilippo gene therapy clinical trials underway today, a harmless virus is used to carry the healthy gene into the body. Professor Haiyan Fu has developed a second-generation gene therapy that has been modified with the hope of increasing its effectiveness.
A preclinical study by Prof. Haiyan Fu and her team was performed with funds from the Sanfilippo community through the Aislinne’s Wish Foundation and the Abby Grace Foundation.
In this study, the virus carrying the healthy SGSH gene was administered via a single intravenous injection into Sanfilippo type A mice between one and six months of age.
This led to rapid and long-term production of the sulfamidase enzyme and the improvement of Sanfilippo symptoms in the mice tested - including significantly improved behaviour up to six months after injection.
Excitingly, they found that even the older Sanfilippo mice responded to the treatment, but took longer to respond compared to the younger mice. 80% of the mice treated at 6 months* of age lived as long as the non-Sanfilippo mice, and no adverse effects were observed in any of the groups of mice. When the first-generation gene therapy was tested in four-month-old mice by another group of researchers, no significant improvement in cognition was seen. In comparison, results using this second-generation therapy indicate significant improvements in cognition and motor function over time in the mice treated at six months of age. It is not until clinical studies are completed whether we will know if the results are reproducible in humans.
The experiments confirmed the greater efficiency of this new gene therapy, with a lower dose being required to generate a therapeutic effect - half of the dose compared that of earlier gene therapies for Sanfilippo type A.
Further work will be completed with continued funding from the Abby Grace Foundation, and in collaboration with Cure Sanfilippo Foundation. While timing depends on many factors, there is hope to start a trial in 2021.
*Note that healthy mice only live for around two years so mouse age is not equivalent to human age.