Foundation-funded translational research identifies dopaminergic drug that improves autism symptoms and helps restore dopamine-receptor activity in the Sanfilippo A mouse model

April 29, 2024

The research project further investigated the impact of altered heparan sulfate (HS) metabolism on brain development and its contribution to dementia-related protein aggregation Sanfilippo mice

A two-year translational grant made in 2021 by Cure Sanfilippo Foundation, Sanfilippo Fighters (Italy), and Sanfilippo Children’s Foundation (Australia) to Elvira De Leonibus, PhD, with postdoc Maria De Risi of Telethon Institute of Genetic Medicine (TIGEM) has been completed.

Previous research by Dr. De Leonibus’ group, funded by Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation, found there is an increased proliferation of dopaminergic cells in Sanfilippo Type A mice during embryonic neurodevelopment, which is not due to a loss of lysosomal function, but rather a loss of heparan sulfate function. It also found that autistic symptoms in MPS IIIA mice can be improved by correcting the dopamine receptor imbalance that is uniquely found in Sanfilippo. Commonly used dopaminergic drugs in the category of atypical antipsychotics, like risperidone, have been reported to have increased undesirable extrapyramidal side effects in individuals with Sanfilippo syndrome. Thus, identification of effective medications to treat behavioral symptoms of disease with less side effects is greatly needed.

To address this need, Dr. Leonibus and her team tested two drugs that act in different ways on the dopamine system, to see which can best address behavioral symptoms without adverse side effects. Short term and long term experiments were conducted beginning with mice as early as 2 months of age. Both drugs were able to improve autism symptoms compared to untreated mice. However, one of the drugs appeared to increase the adverse side effect of catalepsy (muscle rigidity and fixed posturing) in the Sanfilippo mice.

The other drug improved autism symptoms without increasing catalepsy. Biochemical tests using this second drug also indicated that it helped to restore the levels of dopamine-receptor activation in the brain to normal levels without an increase in negative side effects.

As expected, neither drug changed levels of heparan sulfate accumulation. Despite being able to address autism symptoms which are characteristic of earlier stages of disease in the mouse model, dementia symptoms progressed in the later stage animals similar to those who did not undergo treatment.

Further work by the team investigated how the altered metabolism of heparan sulfate (HS) affects brain development in Sanfilippo and as the animals age. HS normally plays a role in both the structure, or scaffolding, in the brain, as well as assisting in signaling between brain cells to support growth. Partially-degraded HS, which builds up in Sanfilippo due to an enzyme deficiency, has been shown by the team to disrupt these normal processes. By looking at the HS in the brains of mice with and without Sanfilippo type A at birth, at two months and eight months of age, they saw differences in the structure and function of HS in the Sanfilippo samples over time. This work indicates that Sanfilippo not only increases the amount of HS by-products, but also affects the structure and function of HS in the brain, including the function of HS in important brain development pathways and its interaction with proteins that can clump together and are associated with adult-onset dementias.

The team is working on a manuscript to share their results with the research community. Their data advances the field with a greater understanding of the impacts of HS structure and function. The work in this project may also assist in developing a clinical trial to investigate drugs that can target the behavioral symptoms in Sanfilippo based on the now uncovered role of HS in dopamine receptor imbalance.

See full details about the research project

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