Targeting autophagy as a therapeutic strategy for Sanfilippo

The Sanfilippo Children’s Foundation has awarded funds to the Telethon Institute of Genetics and Medicine (TIGEM) in Italy for a research project that will target a process called “autophagy”, which is the process that clears unnecessary or dysfunctional components from cells. The team led by Dr Ivan Conte and Dr Nicolina Cristina Sorrentino will study an autophagy activating drug and investigate if this approach could be developed into a treatment for Sanfilippo Syndrome.

Sanfilippo Syndrome is caused by the deficiency of one of the enzymes required to break down a complex sugar called heparan sulfate. This heparan sulfate then accumulates in all tissues (especially in the brain) causing damage. It is hoped that by activating autophagy, toxic heparan sulfate will be cleared out, allowing the cells to function better. This approach has shown promise in a mouse model of a related disease called MPS VII (also called Sly Syndrome).

“Scientists are now tackling Sanfilippo from every angle, from replacing the missing enzyme and gene therapy to substrate reduction and chaperones. This project adds another string to our bow in the fight for a cure. If successful, targeting autophagy could complement other therapies being developed and may be especially helpful for older patients to help clear out the large amount of accumulated substances in their cells and hopefully improve their quality of life” said Megan Donnell, Executive Director of the Sanfilippo Children’s Foundation.

The first aim of the project will be to understand the autophagy pathways in Sanfilippo a bit better before testing a drug candidate that targets autophagy in cells grown in the laboratory and mouse models of the disease. The drug candidate was previously identified by cancer researchers, and since some preclinical data is available on this drug, relatively quick translation to clinical trial may be possible.

Dr Ivan Conte’s research group at TIGEM uses cellular and animal models to study autophagy in eye diseases and is now interested in studying autophagy in neuronal cells in order to develop new therapies for neurodegenerative disorders such as Sanfilippo Syndrome.

Dr Nicolina Cristina Sorrentino is Head of the Preclinical Core Facility at TIGEM. She has been researching therapies for Sanfilippo Syndrome since 2007, in particular gene therapy and enzyme replacement therapy.

Project Update

Dr Ivan Conte and Dr Nicolina Cristina Sorrentino have completed their Incubator grant focused on autophagy as a therapeutic strategy for Sanfilippo. The team mapped out important steps in the autophagy pathway and investigated key molecules involved in controlling autophagy.

Armed with this new knowledge, they tested a drug candidate of interest in Sanfilippo type A patient cells and confirmed that it activates the autophagy process. Using a type A mouse model, the drug candidate was administered daily through the abdomen until mice were nine months of age. Treated type A mice observed improved autophagy compared to untreated mice, along with reduced inflammation. However, there was no reduction in Heparan Sulfate accumulation nor improved behaviour seen in the mice.

Alongside this work, the team characterised retinal degeneration found in the eyes of Sanfilippo type A mice, which is also found in patients, and published a research paper on their findings. Dr Conte and Dr Sorrentino are undertaking further research into the pathophysiological role of autophagy in Sanfilippo type A. While the preliminary results using this autophagy-activating drug indicate it may not be suitable alone, it may be a useful adjunct to other therapies like gene therapy.

Project Summary

  • Chief investigators: Dr Ivan Conte and Dr Nicolina Cristina Sorrentino
  • Project title: Pharmacological induction of autophagy as a novel therapeutic strategy for MPS-IIIA
  • Amount: $90, 000
  • Duration: 1 year
  • Location: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
  • Status: Complete
  • Start date: March 2019

View all funded projects