The Sanfilippo Children’s Foundation has awarded funding to a project at the University of Queensland led by Associate Professor Vito Ferro to design drugs to treat Sanfilippo Type A. The type of drug they hope to discover is called a "pharmacological chaperone".

Sanfilippo Type A (also known as MPS IIIA) results from changes (mutations) in a gene that contains the instructions to produce a protein (or enzyme) called “SGSH” that normally breaks down complex sugars known as GAGs. Children with Sanfilippo type A either do not produce any SGSH protein or the protein that is produced is unstable and does not work well, resulting in GAGs building up and causing damage, especially in the brain.

This new research project is using an approach called “Pharmacological Chaperone Therapy” (PCT) to help SGSH work better in children with Sanfilippo type A. PCT uses a small molecule drug (a “chaperone”) that has been specially designed to attach to the defective protein and stabilize it so it can do its intended job: to break down stored GAG. This approach has recently been successfully used to treat a similar condition called Fabry disease.

The research will involve state-of-the-art computer programs to help design molecules with the required characteristics to act as chaperones. The three-dimensional structure of SGSH has recently been determined, which allows the researchers to use this approach and increase chances of success. They will then chemically synthesize the designed molecules and assess their binding to SGSH in biochemical tests. The most promising molecules will then be tested on cells from patients with Sanfilippo Type A grown in the lab, to determine whether they can reduce GAG levels inside the cells.

This approach will not work for all children with Sanfilippo Type A; it will only work for those with certain mutations in the SGSH gene that result in SGSH protein being produced that is unstable because it is folded incorrectly. It is thought that it may be useful for around 40 to 50% of children. However, there is interest in using chaperones in conjunction with enzyme replacement therapy to stabilise the enzyme until it reaches where it is needed inside the cell, and this could be applicable to all children with Sanfilippo Type A.

An advantage of this approach is that this type of drug is usually easy and cheap to manufacture, and because they are small, they can get inside the cells easily. They can also often be engineered to pass through the blood-brain barrier and to be suitable for taking orally. By contrast, treatments such as gene therapy and enzyme replacement therapy are generally more expensive and complicated to administer (usually injected or infused into the blood or sometimes directly into the brain).

Megan Donnell, executive director of the Sanfilippo Children’s Foundation, said: “We are excited to be funding Australian researchers to use cutting-edge technology to search for new treatments for Sanfilippo. If an effective chaperone drug is found, it could make a difference to children with Sanfilippo on its own and may enhance treatments already being developed such as enzyme replacement therapy.”