Drug Development.

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Alpha-synuclein (aSyn) aggregates are implicated in Parkinson Disease (PD) and other synucleinopathies.
• Familial PD mutations accelerate aSyn aggregation, leading to neurodegeneration and motor deficits in mouse models.
• aSyn and tau aggregates are also found in Alzheimer Disease (AD).

Purpose of the Study:

• To evaluate the efficacy of CNS11g, a small molecule therapeutic candidate, in a mouse model of PD.
• To assess CNS11g's ability to disaggregate pre-existing alpha-synuclein and tau fibrils.
• To determine the safety and therapeutic potential of oral CNS11g in late-stage disease.

Main Methods:

• Heterozygous A53T M83 mice, aged 24 months, were treated with CNS11g via oral gavage for 6 weeks.
• The study measured brain levels of CNS11g, motor function, and levels of soluble and insoluble aSyn and tau aggregates.
• Western blot and immunohistochemistry (ICC) were used to quantify protein aggregates and neuroinflammation.

Main Results:

• Oral CNS11g achieved therapeutic brain concentrations and ameliorated motor deficits without toxicity.
• CNS11g reduced soluble, high molecular weight aSyn aggregates and tau oligomers in the spinal cord and brainstem.
• ICC showed reduced aSyn deposits, but biochemical analysis did not confirm a reduction in insoluble fibrillar aSyn.

Conclusions:

• Late-stage oral administration of CNS11g demonstrates safety and efficacy in reducing motor deficits and specific protein oligomers.
• The drug exhibits pleiotropic central nervous system activity against alpha-synuclein and tau oligomers.
• Further studies with higher or longer dosing may be needed to clear insoluble fibrils.