The Sanfilippo Children’s Foundation has awarded funds to the Telethon Institute of Genetics and Medicine (TIGEM) in Italy for a research project that aims to improve the effectiveness of gene and enzyme replacement for Sanfilippo Syndrome. The team led by Dr. Alessandro Fraldi will search for enzymes that can more efficiently degrade the toxic heparan sulfate that builds up inside the cells of children with Sanfilippo.
Sanfilippo Syndrome is caused by the deficiency of one of the enzymes required to degrade a complex sugar called heparan sulfate. This heparan sulfate then accumulates in all tissues (especially in the brain) causing damage.
The most promising therapeutic approaches for the treatment of Sanfilippo Syndrome are based on the replacement of either the missing enzyme (enzyme replacement therapy) or the gene responsible for making that enzyme (gene therapy). Maintaining high enough levels of the replaced enzyme, especially in the brain, is proving to be a challenge for these approaches.
In this project, the researchers will search for enzymes that are able to degrade heparan sulfate even more efficiently than the natural enzyme present in people without Sanfilippo. These are called ‘super active’ enzymes and if successful could increase the effectiveness of gene and enzyme replacement therapies and/or lower the dose required, thus improving their safety. This approach has been successful for conditions such as haemophilia.
The enzyme missing in Sanfilippo Syndrome Type A – sulfamidase – will be the target in this project and if successful this approach could be applied to the other subtypes. The researchers will artificially produce in the lab thousands of variants of the sulfamidase enzyme, each with small random changes to its structure. Sophisticated high throughput screening methods will then be used to select potential ‘super active’ enzymes.
“Therapies that treat the root cause of Sanfilippo – gene therapy and enzyme replacement therapy – are so promising but there is still more work to be done to optimise them for maximum benefit for patients. This project is exploring one way to potentially boost these approaches and allow next generation therapies to enter clinical trials,” said Megan Donnell, Executive Director of the Sanfilippo Children’s Foundation.
Dr Alessandro Fraldi leads the Molecular Therapy research group at TIGEM. His interest includes the study of mechanisms underlying the neuropathogenesis of lysosomal storage disorders and developing new therapeutic approaches for the treatment of these disorders.
- Project title: Generation of “super active” variants of lysosomal enzymes to treat the CNS in Sanfilippo Syndrome
- Chief investigator: Dr. Alessandro Fraldi
- Amount: $90, 000
- Duration: 1 year
- Location: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Status: Active
- Start date: March 2019