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A Pre-Clinical Study in a PD-like Transgenic Pre-Clinical Model of a Novel Isoindole Compound that Selectively Blocks Alpha-Synuclein Oligomerization

The damage to neuronal cells and connections in Parkinson’s disease is associated with the abnormal accumulation of a neuronal protein denominated alpha-synuclein. We have developed powerful simulations programs and utilizing Supercomputer center at UCSD we have modeled the abnormal ?-synuclein. Utilizing this state of the art approach we developed and synthesized a series of new compounds that hold the promise for the treatment of Parkinson’s Disease by blocking alpha-synuclein.

Project Description: 
The main objective will be to investigate in a pre-clinical model of Parkinson’s disease the beneficial effects of the alpha-synuclein blocking developed at UCSD and Neuropore Therapies. For this purpose, we will at first investigate the time course and dose response for the compound distribution in blood and in the brain in the pre-clinical model. Based on this information the ideal two doses will be selected for a more comprehensive study in our genetic pre-clinical model of Parkinson’s disease. The model will be evaluated for beneficial effects of the compound compared to control on motor and memory tests. Then we will investigate the effects of the compound at rescuing the neuronal connections and at blocking the accumulation of alpha-synuclein.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
Most treatments available for Parkinson’s disease are Symptoms & Side Effects, however no therapies exist that will control or stop the progression of the disease. Since the compounds we discovered are designed to block the accumulation of toxic alpha-synuclein aggregates they have the potential of slowing the disease allowing recovery. The compounds we propose to test represent a “disease modifying” therapy for Parkinson’s disease.

Anticipated Outcome: 
The main objective will be to obtain proof-of concept in an animal model of Parkinson’s Disease for the therapeutical effects of our ?-synuclein blocking compound. We will investigate if our compound reduces the parkinson’s like behavior and accumulation of toxic proteins in the brain. This study will provide information for the dose and time course for treatment. Most drugs fail because they can’t get into the brain. The information obtained by this study is critical in demonstrating the effective concentration of the drug and its capacity to cross into the brain.

Final Outcome

NPT-100-18A (AKA IIPP-1), was designed to bind to a critical binding region of alpha-synuclein.  Preliminary in vivo assessments demonstrated that NPT-100-18A administration lowers a-synuclein levels and improve motor performance in a transgenic model of Parkinson’s disease.  The project objectives were to (Year 1) evaluate the PK properties of NPT-100-18A, and (Year 2) to conduct in vivo efficacy studies with motor behavioral performance, biochemical and neuropathological endpoints.  

Year 1 PK evaluations demonstrated no safety issues with NPT-100-18A and provided information regarding doses to use in Year 2 studies.  In vivo efficacy studies conducted in Year 2 demonstrated that NPT-100-18A (10 & 20 mg/kg) improved motor measures and normalized neuropathology in a pre-clinical model of Parkinson’s disease.  Taken together, the project study results support further evaluation of compounds (like NPT-100-18A) targeting a-synuclein as a therapeutic strategy for synucleinopathy disorders including Parkinson’s disease.


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