State of play: Development of therapies targeting autophagy in Sanfilippo

29 Sep 2022

Sanfilippo syndrome is a genetic condition that leads to an enzyme deficiency. It affects the whole body, however the greatest impact is on the brain. The condition ultimately leads to dementia and death before the individual has reached adulthood.

Currently, no approved treatment options are available. While researchers are working to restore the enzyme absent in Sanfilippo (e.g. through gene and enzyme replacement approaches), other therapeutic avenues aim to tackle and slow down some of the secondary effects that contribute to cell damage and disease symptoms.

Autophagy dysfunction is one secondary effect in Sanfilippo, and researchers are working to develop therapies that can target autphagy.

What is autophagy and how is it involved in Sanfilippo?

Autophagy, which translates to ‘self eating’, is a process that removes and recycles cell components that are not required or are no longer working. Acting as a ‘housekeeper’ of the cell, autophagy is a natural process important for healthy cell function. It is especially crucial in the brain as neurons do not replicate or renew themselves, and these cells must survive throughout a person’s lifetime.

In Sanfilippo, a lysosomal storage disorder, toxic molecules overwhelm the lysosomes, which are compartments inside cells that are critical for the autophagy process. Researchers have found that autophagy is impaired in Sanfilippo and contributes to the ongoing toxic build-up of molecules seen in the disease. 

What are the benefits of targeting autophagy?

By activating or restoring autophagy, it may be possible to help clear the build-up of heparan sulfate and other molecules in Sanfilippo, to restore the cell’s recycling and housekeeping functions. This could potentially slow neurodegeneration and improve the neurological symptoms of the disease.

There are four subtypes of Sanfilippo, and often other approaches, like gene therapy, focus only on one subtype. However, a drug that successfully activates autophagy in Sanfilippo could be used by all Sanfilippo patients. It might also be used for other neurodegenerative diseases, including other childhood dementias and adult-onset dementias.

A drug that targets autophagy may be a small molecule, which can be synthesised more cheaply than other complex therapies like gene therapy and enzyme replacement therapy. Also, small-molecule drugs can be modified to improve their ability to reach the brain or to be taken orally.

Autophagy dysfunction is common among many neurodegenerative diseases, and therapies targeting autophagy are under investigation for other dementias like adult-onset Alzheimer’s disease and Parkinson’s disease. Due to the similarities in autophagy dysfunction, an effective autophagy-promoting drug for one of these neurodegenerative diseases may be useful for another. In Australia, the TGA has approved an autophagy-promoting drug for patients with the disease Tuberous Sclerosis Complex, which involves a change in one of two genes involved in the regulation of autophagy. There are also drugs available for other disorders that have been shown to act on the autophagy pathway, but these need to be investigated further for their potential in neurodegenerative diseases. 

What are the challenges of targeting autophagy?

The main drawback of autophagy-promoting drugs is that they do not target the root cause of Sanfilippo; that is, the changes in the gene, or the non-functional enzyme, which leads to the build-up of heparan sulfate. Because of this, it may be best used in addition to other approaches that do target the root cause of the disease, such as gene therapy. Combining another therapy with an effective autophagy-promoting drug may produce even better treatment outcomes than using either treatment alone.

Potential autophagy-promoting drugs for Sanfilippo would need to be taken long-term and are not a once-off treatment. Therefore, any drug candidates must be carefully tested to ensure they don’t cause toxicity and adverse side effects in the patient. Other potential therapies, like enzyme replacement, pharmacological chaperone, substrate reduction, or anti-inflammatory therapies, would also require regular administration. 

If researchers identified a potential autophagy-promoting 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.

There is also concern regarding the benefit of activating autophagy in certain diseases, including lysosomal storage disorders like Sanfilippo: if the lysosomal function is impaired, activating autophagy may lead to a build-up of autophagosomes and their contents that cannot be broken down. Further research is needed on autophagy activation in Sanfilippo and similar diseases to see if this is the case.

What is the state of play for research into autophagy-promoting therapies for Sanfilippo?

A clinical trial of Trehalose for Sanfilippo is currently being planned by Seelos Therapeutics and Team Sanfilippo Foundation (USA). Trehalose is a small sugar that has been reported to cross the blood-brain barrier. It is hoped Trehalose will promote autophagy, but also stabilise proteins and enhance lysosome function.

Other approaches to targetting in other neurological conditions similar to Sanfilippo have also been tried or are being investigated. Some examples of research funded by the Sanfilippo Children’s Foundation in this area include:

The Sanfilippo Children’s Foundation and Fondation Sanfilippo Suisse awarded funds to Dr. Louise O’Keefe in 2019 to use fruit fly models of Sanfilippo type A and C to study autophagy. 

Dr Ivan Conte and Dr Nicolina Cristina Sorrentino were awarded an Incubator grant in 2018 to investigate autophagy as a therapeutic strategy for Sanfilippo. 

In 2020, a team led by Associate Professor Alessandro Fraldi, Prof. Gal Bitan and Prof. Thomas Schrader received a Translational grant from the Sanfilippo Children’s Foundation, Cure Sanfilippo Foundation and the H.A.N.D.S. consortium to further investigate CLR01, which has previously been shown to relieve autophagy-lysosomal dysfunction in a mouse model of Sanfilippo type A. This work is ongoing.


  • Treatments targeting the process of autophagy in the cell are a potential therapeutic avenue for Sanfilippo.
  • For patients with Sanfilippo, autophagy-promoting drugs aim to clear molecules like heparan sulfate that build up in the disease.
  • Autophagy-promoting drugs do not address the underlying cause of Sanfilippo, but could potentially slow disease progression.
  • There are therapies targeting autophagy currently under investigation for Sanfilippo in Australia and worldwide.

More information on different therapy avenues currently in, or close to, a clinical trial can be found on our website: