The “molecular tweezer” CLR01 as a new potent drug candidate to slow CNS pathology progression in MPS-I
Awardee: Alessandro Fraldi
Institution: University of Naples "Federico", Dept of Translational Medicine
Award Amount: $65,040
Funding Period: February 1, 2021 - January 31, 2022
Summary:
Progressive neurological deterioration characterizes both severe (Hurler) and intermediate (Hurler-Scheie) forms of MPS-I. Unfortunately, to date, there is no treatment for the CNS pathology in MPS-I patients.
Under different stress conditions, certain aggregation-prone proteins misfold and self-assemble into neurotoxic insoluble deposits called amyloids. Aggregation and deposition of amyloid proteins in the brain is a hallmark of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. By studying mouse models of Sanfilippo syndrome we have recently shown that deposition of amyloid proteins also occurs in the brain of these mice and is a key event contributing to the neurodegenerative processes. Furthermore, extending previous observations, we have shown that similarly to the Sanfilippo syndrome, amyloid deposition also occurs in the brain of other mouse models of MPS and, in particular, is associated to neurodegenerative processes in the brain of post-mortem patients with MPS-I.
To counteract these amyloid-mediated pathological processes, we made use of a potent and specific inhibitor of amyloid protein aggregation known as CLR01. CLR01 is a lead compound of the “molecular tweezers” class of small molecules that act by a unique mechanism to efficiently inhibit abnormal self-assembly of multiple amyloidogenic proteins. CLR01 has been shown to be effective in protecting against neurodegeneration in mouse models of Alzheimer’s and Parkinson’s diseases. Moreover, previous studies also have shown that CLR01 has a wide safety margin in mice and crosses the blood-brain barrier when administered systemically. We have shown that subcutaneous injection of CLR01 in the mouse model of MPS-IIIA, the most and severe form of Sanfilippo syndrome resulted in a striking reduction of amyloid protein deposition in the brain and correction of neuropathological phenotype, including cognitive function.
Here we want to extend the proof of efficacy of CLR01 beyond MPS-IIIA and test the hypothesis that inhibiting amyloid deposition by CLR01 is an effective therapeutic option to slow CNS manifestations in MPS-I forms with CNS involvement. Overall our results may open the possibility to develop effective CNS therapies for MPS-I based on parenteral administration of CLR01, a drug with a unique mechanism of action and with a high translational potential.