Targeting misfolded proteins for therapy for Sanfilippo Type C

The Sanfilippo Children’s Foundation has awarded funding to a project at University Hospital Centre Sainte-Justine in Montreal, Canada. The project will be led by Professor Alexey Pshezhetsky, who has been working on Sanfilippo and other related conditions for many years, and this funding will allow him and his team to continue their work on developing chaperone drugs for Sanfilippo Type C, aka MPSIII C.

Dr Pshezhetsky’s lab was the first to discover the gene causing Sanfilippo Type C, which is called “HGSNAT” and create a mouse model of the disease. The HGSNAT gene contains the instructions to produce a protein (or enzyme) that normally breaks down complex sugars called mucopolysaccharides (also known as GAGs).  Children with Sanfilippo Type C either do not produce any HGSNAT protein or the protein that is produced is folded incorrectly and does not work, resulting in GAGs building up and causing damage, especially in the brain.  

Previous work by the team of Dr Pshezhetsky discovered that small molecules called chaperones could help the HGSNAT protein to fold correctly and partially restore its function. This work was done in Sanfilippo Type C patient cells grown in the laboratory. This new project aims to improve the chemistry of these HGSNAT chaperones and test if they can reduce the symptoms in mice with Sanfilippo Type C. They will see if the behaviour, memory and life span of the mice can be improved. If any of the drugs can show a benefit in the mouse model, this will open the door for testing in children with Sanfilippo in a clinical trial.

This approach will not work for all children with Sanfilippo type C: it will only work for those with certain mutations in the HGSNAT gene that result in incorrectly folded protein. However, it is thought that at least fifty percent of patients may be able to benefit from this approach and it is known that only a small amount of enzyme activity is needed to alleviate the symptoms of Sanfilippo type C, which makes it a good candidate for chaperone therapy. 

An advantage of this chaperone approach is that these types of drugs are 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). 

Professor Pshezhetsky said: "I am truly grateful to the Foundation for this grant. The advantage of chaperone therapy for Sanfilippo disease that we are developing is that it will not only benefit patients before they start developing clinical symptoms but may also ameliorate disease and improve quality of life for the patients in advanced stages of the disease."  

Project Update

Prof. Alexey Pshezhetsky’s project Targeting misfolded proteins for therapy of Sanfilippo type C has been completed. In the study, the team of researchers tested various molecules to find chaperones for Sanfilippo type C using patients’ cells and a mouse model. Two molecules showed potential when tested with two different type C patient fibroblast cell lines. The most promising of these was tested with cultured skin fibroblasts of Sanfilippo type C mice, which further supported its chaperone potential. As the lead candidate is orally available, it was provided in the drinking water to mice at three weeks of age. Compared to untreated mice, the Sanfilippo type C mice that consumed the molecule displayed significantly improved memory in two behavioural tests. Prof. Pshezhetsky and his team are continuing their work to find chaperones for Sanfilippo type C. If results in further tests are promising, a clinical trial may be planned to determine whether the best candidate can improve disease symptoms in patients.

You can read more about the results of Professor Pshezhetsky’s project on our website here.

Professor Alexey Pshezhetsky is a biochemist who did his training and early research in Moscow, moving to Montreal in 1992. A major research focus of Dr Pshezhetsky is lysosomal storage disorders, and in particular Sanfilippo. 

Project Summary 

  • Chief investigator: Professor Alexey Pshezhetsky
  • Project title: Targeting Missfolded Proteins for Therapy of MPSIIIC
  • Amount: $98K (over 1 year)
  • Location: Montreal, Canada
  • Status: Complete
  • Start date: February 2018