State of play: Development of chaperone therapies for Sanfilippo

05 Aug 2021

There are currently no approved treatment options for Sanfilippo Syndrome, but several therapeutic avenues are being explored. Gene therapy and enzyme replacement therapy are most often talked about, but Pharmacological Chaperone Therapy, or PCT, is another promising avenue under development.

What is chaperone therapy?

In some patients with genetic diseases, the enzyme involved is produced, but it has structural changes that make it unstable. As a result, the enzyme is broken down before it reaches the part of the cell where it is needed to do its job. This leads to the build-up of a waste product such as heparan sulfate (HS), as seen in Sanfilippo. PCT involves drugs that bind to and stabilise the enzyme, allowing it to reach its destination and perform its job.

What are the benefits of chaperone therapy?

Chaperone drugs have the potential to address the enzyme deficiency at the heart of Sanfilippo. By stabilising the enzyme and allowing it to degrade HS in the cell, it may be possible to minimise or even halt disease progression. 

Chaperone drugs are usually small molecules, meaning they can be synthesised more cheaply than other complex therapies like gene therapy. Also, small-molecule drugs can be modified to improve their properties; for example, their ability to reach the brain or be taken orally.

One example of a chaperone drug that has been developed and approved for other diseases is Galafold® (also known as Migalastat). This treatment is approved by Australia’s Therapeutic Goods Administration (TGA) for use in Fabry disease. Like Sanfilippo, Fabry is a lysosomal storage disorder that involves the build-up of material due to an enzyme deficiency.

What are the challenges of chaperone therapy?

Chaperone drugs target specific enzymes, so different chaperones are required for the different Sanfilippo subtypes. 

A chaperone drug that works for one Sanfilippo patient may not be suitable for another patient even with the same subtype. This is because chaperone drugs target specific changes in the enzyme structure, and these changes can differ between patients. Because of this, PCT may require a more personalised medicine approach to find the right drug for an individual patient. 

Another issue is that a chaperone drug is not a single dose treatment and must be taken long-term. Any potential PCT drugs must be carefully tested to make sure they don’t cause toxicity and adverse side-effects in the patient. 

If researchers identified a potential chaperone drug for Sanfilippo, preclinical studies in animals would be required before a clinical trial can take place. How long these studies might take would depend on many factors, such as whether the drug is completely new, or whether it is an existing drug that has already been tested in animals or humans.

What is the state of research into chaperone therapy for Sanfilippo?

There are researchers around the world working to develop potential chaperone therapies for Sanfilippo, including:

For type A:

Associate Professor Vito Ferro, at the University of Queensland, Australia, commenced an Incubator project to develop potential PCT drugs for Sanfilippo type A in 2018. The project identified candidate drugs that are now undergoing testing in mice in a Translational project led by Dr Adeline Lau and co-funded by SCF and Fondation Sanfilippo Suisse (Switzerland).

For type B: 

In late 2020, Associate Professor Ferro received an Incubator grant from SCF, Fundacja Sanfilippo (Poland) and Sanfilippo Initiative (Germany), to build on work started with funding from Bulgarian donors,  to develop chaperones for type B. This project is ongoing.

A recently published study led by Prof. Matthieu Sollogoub and Prof. Yves Blériot of France, identified potential chaperones for the type B enzyme, NAGLU. Their most promising candidate was able to increase the activity of NAGLU by nearly two and a half times. More research is needed to follow-up on this finding. 

For type C: 

Professor Alexey Pshezhetsky of the University of Montreal, Canada, received an Incubator grant from SCF in 2017 to develop chaperone drugs for Sanfilippo type C. The team tested a potential candidate that can be taken by mouth, with promising initial results seen in type C mice. This work built on Prof. Pshezhetsky’s previous work on type C chaperones, including a project funded by Cure Sanfilippo Foundation (USA). 

Development of chaperone drugs can be made easier with a better understanding of the physical and chemical ‘shape’ of the target enzyme. While the structure of the type A and B enzymes have been discovered, it is only recently that this work has been pursued for type C. Pharmaceutical company Phoenix Nest, Inc. have been collaborating with the University of California San Diego with the help of a US National Institutes of Health grant to do this work and develop a type C chaperone therapy.

For type D: 

There are currently no PCT lines of investigation that we are aware of for Sanfilippo type D.


  • Pharmacological Chaperone Therapy (PCT) is a possible therapeutic avenue for Sanfilippo
  • For Sanfilippo, PCT aims to stabilise the faulty enzyme so it can break down heparan sulfate in the cell
  • PCT drugs have been successfully developed for other diseases
  • A PCT drug that works for one Sanfilippo patient may not be suitable for another
  • PCT development is an active area in Sanfilippo research in Australia and around the world