Screening of potential therapeutics affecting lysosomal acidification in a fruit fly model of Sanfilippo

The Sanfilippo Children’s Foundation and the H.A.N.D.S. consortium (Associação Sanfilippo Portugal, Sanfilippo Barcelona, Sanfilippo Sud) have awarded an Incubator Grant to Associate Professor Michael Lardelli at The University of Adelaide. The project will investigate the extent to which the pH (acidity) of the lysosome is affected in Sanfilippo using a fruit fly model of the disease and investigate whether targeting lysosomal acidity might be useful for treating the disease.

The build-up of heparan sulfate is a defining feature of Sanfilippo syndrome that has severe consequences for the function of lysosomes, compartments inside cells that help to degrade and recycle waste products. 

Usually, the environment inside lysosomes is highly acidic to help break down molecules; however, A/Prof Michael Lardelli and his team have found evidence for a reduction in the acidity of lysosomes in a zebrafish model of Sanfilippo type B.

The investigators plan to use a fruit fly model of Sanfilippo type A or type B to continue to investigate how the acidity of lysosomes is impacted in Sanfilippo. They will also determine whether therapies targeting lysosomal acidity can improve symptoms of the disease.

First, they will develop a genetically-modified fruit fly model of Sanfilippo type A or B specially designed to test the acidity of lysosomes. The model will be engineered to include proteins that fluoresce different colours with changes in lysosomal pH, allowing acidity to be easily measured. Fruit flies are a widely used animal model in research – they are relatively easy and cheap to grow and study in the lab, and they allow sophisticated yet relatively easy genetic manipulations to study diseases like Sanfilippo.

The team will also monitor the flies for the behavioural and sleep issues that reflect the symptoms of Sanfilippo, and measure their lifespan. Finally, the team will test if drugs that increase the acidity in the lysosomes can improve symptoms. Drugs will be placed in the food of the fruit fly, and behavioural, sleep, lifespan, and lysosomal acidification tests will be repeated to see if any drugs may have therapeutic potential.

The study may identify a new therapeutic avenue for Sanfilippo that could lead to future therapies, and although type A or B fruit flies will be used in the study, the findings could likely be applied to all types of Sanfilippo.

“The team in this project are well-versed in the use of model organisms to investigate disease mechanisms in Sanfilippo and test potential therapeutic candidates,” said the Head of Research of the Sanfilippo Children’s Foundation, Dr Lisa Melton. “Understanding these mechanisms and how they contribute to the development of symptoms is essential to develop effective therapies.”

Associate Professor Michael Lardelli has over 33 years of experience as a geneticist, with the last 20 of those involved in Alzheimer’s Disease research which led him towards research into Sanfilippo syndrome. Throughout his research career, he has used fruit fly and zebrafish models, coupled with cutting-edge genetic techniques, to answer key questions about human diseases.

Project Summary

  • Project title: A Drosophila MPS III mutation model for screening of potential therapeutics affecting lysosomal acidification
  • Chief investigator: Associate Professor Michael Lardelli 
  • Amount: $20,000, including 6,000 € from the H.A.N.D.S. consortium (Associação Sanfilippo Portugal, Sanfilippo Barcelona, Sanfilippo Sud)
  • Duration: 1.5 years
  • Location: The University of Adelaide
  • Status: Active
  • Start date: February 2023

* Types A or B will be studied in this project, but findings may be applied to all types of Sanfilippo

View all funded projects