The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Journal article

Mucopolysaccharidoses (MPSs) are childhood diseases caused by inherited deficiencies in glycosaminoglycan degradation. Most MPSs involve neurodegeneration, which to date is untreatable. Currently, most therapeutic strategies aim at correcting the primary genetic defect. Among these strategies, gene therapy has shown great potential, although its clinical application is challenging. We have shown previously in an MPS-IIIA mouse model that the molecular tweezer (MT) CLR01, a potent, broad-spectrum anti-amyloid small molecule, inhibits secondary amyloid storage, facilitates amyloid clearance, and protects against neurodegeneration. Here, we demonstrate that combining CLR01 with adeno-associated virus (AAV)-mediated gene therapy, targeting both the primary and secondary pathologic storage in MPS-IIIA mice, results in a synergistic effect that improves multiple therapeutic outcomes compared to each monotherapy. Moreover, we demonstrate that CLR01 is effective therapeutically in mouse models of other forms of neuronopathic MPS, MPS-I, and MPS-IIIC. These strongly support developing MTs as an effective treatment option for neuronopathic MPSs, both on their own and in combination with gene therapy, to improve therapeutic efficacy and translation into clinical application

Authors: Di, J; Siddique, I; Li, Z; Malki, G; Hornung, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Alzheimer's Research & Therapy
• Volume: 13
• Issue: 1
• Pages: 6-6
• Article number: 6
• Publication date: 2021-01-04
• DOI: 10.1186/s13195-020-00743-x
• EISSN: 1758-9193
• ISSN: 1758-9193
• Language: English
• Keywords: Pathology; Presenilin; Neuroscience; Neurodegeneration; Biochemistry; In vivo; Medicine; Transgene; Biology; Alzheimer's disease; Genetically modified mouse; Tauopathy; Chemistry; Tau protein; Disease