Page last updated: Aug. 21, 2024
Page reviewed by: Dr. Cara O’Neill, FAAP
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Cure Sanfilippo Foundation has co-funded a research grant with Sanfilippo Children’s Foundation (Australia) and H.A.N.D.S consortium, an international network of Type C families and groups.
This grant is to Associate Professor Alessandro Fraldi at CEINGE – Advanced Biotechnology, in Naples, Italy. This two-year translational project builds on the team’s previous research on this treatment approach, which was funded by Cure Sanfilippo Foundation, who found protein aggregates in the brains of mice with Sanfilippo types A, B, and C. When they tested the drug candidate CLR01 in young Sanfilippo type A mice, there was significantly reduced aggregation and inflammation in the brain.
“Further studies in MPS-IIIA mice have showed that α-synuclein progressively accumulates together with other amyloid proteins, including PrP, tau, and Aβ mostly into the lysosomes of neuronal cell bodies, thus exerting a gain of neurotoxic function by affecting ALP (Monaco et al., 2020). Indeed, inhibiting amyloid aggregation in MPS-IIIA mice by using CLR01, a “molecular tweezer” that acts as a broad-spectrum inhibitor of protein self-assembly (Attar and Bitan, 2014) reduced lysosomal enlargement and re-activates autophagy, thus ameliorating neurodegenerative signs (Monaco et al., 2020). “
The team will further examine the potential of CLR01 in Sanfilippo, by studying whether pathology and symptoms are improved in Sanfilippo types B and C mice. They will examine whether higher doses and longer treatment can enhance the effects in older type A mice and also compare and combine CLR01 treatment with gene therapy.
“The hope is that with promising results, we can move to a clinical trial for treating children with CLR01,” said Cure Sanfilippo Foundation Chief Science Officer Cara O’Neill, MD, FAAP.
“The generosity of the donors who support the Foundation, its partner-families, and this cause is the reason we are able to continue funding cutting-edge research such as this,” said Foundation President Glenn O’Neill. “Without them, none of this is possible.”
Research Updates
Update – July 2024
Associate Professor Alessandro Fraldi and his team at CEINGE – Advanced Biotechnology in Naples, Italy, have completed their research project supported by a translational grant awarded in 2020 by Cure Sanfilippo Foundation, Sanfilippo Children’s Foundation (Australia), and the H.A.N.D.S. consortium.
They explored their previous findings that the small-drug molecule CLR01 could reduce amyloid aggregation and neuroinflammation in mice with Sanfilippo type A if they were treated at a young age, and they confirmed that CLR01 can prevent amyloid accumulation and neuroinflammation in young mice. But they found that CLR01 treatment alone was ineffective if the mice were treated at an older age when disease pathology was more advanced.
Using the Sanfilippo type A mouse model, they also compared the effects of CLR01 treatment alone and when combined with an AAV9-based gene therapy, which is currently in a clinical trial. They found that the combined treatment led to the best results indicating that the CLR01 treatment could be used to enhance the effects of gene therapy treatments for Sanfilippo.
The team also tested CLR01 in mouse models of Sanfilippo types B and C. The treatment was also able to reduce amyloid aggregation and improve symptoms in these mice, confirming that it could be used for multiple forms of Sanfilippo.
Associate Professor Fraldi and his collaborators, including Prof. Gal Bitan and Prof. Thomas Schrader, are continuing to work on the molecule CLR01 in the treatment of Sanfilippo and explore the potential for testing in a clinical trial. The team is also working on publishing their findings in a scientific journal to share the results with the wider scientific community.