The Sanfilippo Children’s Foundation has awarded funds to Dr. Maria Francisca Coutinho from Dr. Sandra Alves’ lab on Lysosomal Storage Diseases at the National Institute of Health Dr. Ricardo Jorge (INSA) in Portugal. The study will involve developing nanoparticles to deliver substrate reduction drugs to the brain.

Sanfilippo Syndrome results when an enzyme dedicated to the breakdown of a complex sugar molecule called heparan sulfate is faulty. Heparan sulfate then accumulates within the body, resulting in devastating effects especially in the brains of children with Sanfilippo.

A number of approaches are under investigation to develop therapies for the disease, and one of these is Substrate Reduction Therapy (SRT). In Sanfilippo, SRT aims to decrease the production of heparan sulfate so that there is less to build up inside the body. It is hoped that this will improve symptoms and slow disease progression.

One type of potential SRT for Sanfilippo utilises small molecules called small interfering RNA (siRNA). siRNAs are not your traditional drug; they are short pieces of genetic information that switch off or silence genes. For Sanfilippo the siRNA’s would be designed to switch off genes involved in the production of heparan sulfate, and thus help to prevent it’s accumulation. Dr Coutinho’s research has already developed siRNA’s that show potential for Sanfilippo.

While siRNA agents appear as promising therapeutics in a variety of diseases, there are known issues associated with their use: they can be unstable, and it is difficult to deliver them inside cells where they need to work. Before siRNA is considered as a viable treatment option in Sanfilippo, these issues must be addressed.

In this study, Dr. Coutinho and her colleagues will focus on the development of delivery vehicles to get siRNA into cells. These delivery vehicles, called nanoparticles, are essentially miniscule droplets of fat that will enclose the siRNAs, protecting them from degradation. Furthermore, they will be engineered to cross the blood-brain barrier to get them to the brain where they are needed most.

Nanoparticle containing siRNA

The team will make, characterise and compare different nanoparticles to determine which could be the most effective. They will then test the nanoparticles containing the siRNAs on human brain cells in the lab.

Ultimately, the results of this study could benefit not only children with Sanfilippo but also those with other similar conditions. Furthermore, it will help to advance the research landscape as a whole with regards to delivering siRNA into cells.

“This study will help to investigate new approaches to treatment delivery, with an emphasis on drug delivery to the brain. This represents an important step in the drug development process for Sanfilippo”, said Megan Donnell, Executive Director of the Sanfilippo Children’s Foundation.

Dr. Maria Francisca Coutinho is a geneticist who has been studying lysosomal storage diseases, including Sanfilippo, for over 10 years, and has particular interest in the development of Substrate Reduction Therapies for these diseases.

Project Summary

• Project title: Genetic Substrate Reduction Therapy for MPS III: Toward a siRNA-containing nanoparticle targeted to brain cells
• Chief investigator: Dr. Maria Francisca Coutinho
• Amount: $25,000
• Duration: 1 year
• Location: National Institute of Health Dr. Ricardo Jorge (INSA), Portugal
• Status: Active
• Start date: January 2020 

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