Targeting Autophagy for Sanfilippo Syndrome

The Sanfilippo Children’s Foundation and Fondation Sanfilippo Suisse have awarded funds to Dr. Louise O’Keefe from The University of Adelaide and the South Australian Health and Medical Research Institute (SAHMRI). The one-year project will use Sanfilippo Syndrome fruit fly models to study autophagy, a natural process inside cells, which helps to remove and recycle cell components that are not required or no longer working. The project will investigate whether increasing autophagy levels can improve symptoms of Sanfilippo, and which parts of this process could be targeted for the development of future therapeutics.

Sanfilippo results due to a deficiency in one of the enzymes responsible for breaking down heparan sulfate, a complex sugar. Because it cannot be degraded, the heparan sulfate builds up inside the cells to toxic levels.

 One avenue for the treatment of Sanfilippo is to help remove the accumulated heparan sulfate from cells. As a natural cellular process involved in clearing out waste material, autophagy presents as a compelling target for therapeutics. However, the general autophagy process is known to be impaired in Sanfilippo; while this complicates matters, it is hoped that even small improvements could lead to a reduction in symptoms.

This project will study the autophagy process using Drosophila (fruit fly) animal models of Sanfilippo Types A and C. Dr. O’Keefe and her team will increase the levels of autophagy in these flies, and see if this helps to remove heparan sulfate and improve behaviour in the fruit fly. The project will also determine whether specific parts of the autophagy process can be targeted for future therapeutics.

 Dr. O’Keefe and her team developed the world’s first fruit fly model of Sanfilippo Type A (published in 2018), and they found that decreased levels of autophagy led to a worsening of Sanfilippo symptoms. Now, she will build upon this knowledge to determine if increased levels of autophagy can improve symptoms. Fruit flies are a widely used model for investigating genetic diseases and autophagy – they are relatively easy to grow and study in the lab, and the process of autophagy is remarkably similar to that seen in humans.

 Megan Donnell, Executive Director of the Sanfilippo Children’s Foundation, said: “there is currently significant research being undertaken into autophagy as a therapeutic target in a number of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The results of this study will help to identify how autophagy could be targeted to develop therapies for children with Sanfilippo.”

 The Foundation is joined by Fondation Sanfilippo Suisse as a funding partner, contributing a combined AUD$92,000 to this project.

 Dr. Louise O’Keefe is a geneticist at The University of Adelaide and SAHMRI, whose current work focuses on using Drosophila models to investigate dementia-related diseases, including Sanfilippo and Alzheimer’s disease.


Fondation Sanfilippo Suisse and the Sanfilippo Children’s Foundation awarded an Incubator grant to Dr Louise O’Keefe from The University of Adelaide in 2019. Dr O’Keefe and her team used Sanfilippo types A and C fly models to investigate autophagy and determine whether it is a suitable therapeutic target for Sanfilippo.

In the project, fruit flies with genetic changes causing either Sanfilippo type A or C were fed two drugs known to increase autophagy activity in cells. Preliminary tests with one of the drugs in Sanfilippo type A and C fly larvae showed improvements in autophagy inside the larvae’s cells. The same drug was used to treat young adult type A and C fruit flies. The flies underwent behavioural tests to examine their physical activity and neuronal function, and results indicated the drug showed improvements in these tests compared to untreated flies. The second drug did not appear to improve the behavioural symptoms.

In addition to the use of these drugs, the project looked at whether genetic tools to increase the activity of certain autophagy genes would have an effect on disease. Unexpectedly, the team found that increasing the level of products from one autophagy gene was toxic to the fruit flies. This finding needs further investigation, but it may be possible for other key autophagy genes to be targeted instead.

The project has produced important data that will inform future work on the potential of autophagy-targeting therapies in Sanfilippo. Dr O’Keefe’s collaborators plan to publish the results to make the findings available to the wider Sanfilippo research community. They also aim to further explore the potential autophagy enhancing drug in future cell and animal model studies to see whether it has potential as a treatment for Sanfilippo syndrome.  

  • Project title: Targeting Autophagy in Sanfilippo Syndrome
  • Chief investigators: Dr. Louise O’Keefe
  • Amount: $92,000 (co-funded by Fondation Sanfilippo Suisse)
  • Duration: 2 years (extension granted)
  • Location: The University of Adelaide.
  • Status: Completed
  • Start date: February 2020

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