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Effect of NPT088 in Alpha-synuclein Overexpressing Models

This grant builds upon the research from a prior grant: Characterization of NPT001-mediated Alpha-Synuclein Disaggregation and Clearance

Promising Outcomes of Original Grant:
NeuroPhage technology simultaneously targets multiple misfolded proteins (e.g., alpha-synuclein, amyloid-beta, phosphorylated tau) involved in neurodegenerative diseases. The original grant demonstrated that the early drug candidate NPT001 (bacteriophage M13) significantly reduced alpha-synuclein, increased tyrosine hydroxylase and improved motor performance in a pre-clinical model of Parkinson’s disease following a direct-to-brain single injection. NeuroPhage subsequently has identified and isolated the active portion of the bacteriophage that is responsible for its activity against misfolded proteins and termed this region the General Amyloid Interacting Motif (GAIM).  The supplemental research award supports investigation of a second generation candidate, NPT088, in a pre-clinical PD model.

Objectives for Supplemental Investigation:
The second generation drug candidate, NPT088, is a human IgG1 fusion protein that contains GAIM and has demonstrated activity similar to the early lead candidate, NPT001. NPT088 can be dosed systemically, which provides a significant advantage over NPT001, which required administration directly to the brain. In the supplemental research project, a single, dose-level study of NPT088 followed by a multiple dose-level study will be conducted in alpha-synuclein over-expressing transgenic pre-clinical models. Both studies involve chronic, systemic administration of NPT088 and will assess brain pathology and functional improvement. Pharmacokinetic data will also be obtained.

Importance of This Research for the Development of a New PD Therapy:
NeuroPhage’s GAIM approach represents a highly novel and multi-targeted approach to the treatment of neurodegenerative disease such as Parkinson’s disease. The research carried out under this supplemental award will provide important pre-clinical efficacy support for NPT088, a second generation candidate that has significant advantages over the early drug candidate. Positive results will support the continued development of this candidate for the treatment of Parkinson’s disease.

Final Outcome

Two single dose level studies of NPT088 (2 mg/kg and 20 mg/kg) systemically administered weekly for 13 weeks to alpha-synuclein overexpressing Parkinson's disease (PD) model mice provided strong evidence for efficacy, based on reduced brain pathology of drug-treated mice compared to placebo-treated mice. In both studies, the NPT088 treated mice showed significantly higher amounts of a key enzyme required for neurotransmitter synthesis (tyrosine hydroxylase) and significantly lower amounts of aggregated alpha-synuclein, a marker of brain pathology. These results suggest that NPT088 lowered the pathological effects of alpha-synuclein overexpression and resulting pathology in this Parkinson's disease model.

A multiple dose level study (doses of 0.1, 2.0 and 10 mg/kg) has recently completed the drug administration stage to alpha-synuclein overexpressing mice (the same type of mice as in the single dose level study), and the efficacy measurements, including brain pathology and behavior testing results were analyzed. It is now established that treatment with NPT088 did not cause any adverse effects to the mice in either the single dose or the multiple dose level studies, which is a critical prerequisite for continuing the development of this drug candidate. A separate study of the pharmacokinetic behavior of NPT088 in PD models was also carried out, and the data from this study show that NPT088 has similar half-life and distribution in the bodies of PD models and non-PD models.

NPT088 has completed PHASE I testing: http://www.proclarabio.com/our-programs/ 

Oral Presentations in 2015

R. Fisher. Discovery, Preclinical Development and Clinical Trial Approach for NPT088. AAIC 2015, Washington, DC.

R. Fisher. Discovery and Development of NPT088. AD-PD 2015, Nice, France.

R. Fisher. Discovery, Preclinical Development, and Clinical Trial Approach for NPT088, a General Amyloid Interaction Motif (GAIM)-Immunoglobulin Fusion. CTAD 2015, Barcelona, Spain.

R. Fisher. Novel Strategies to Target Misfolded α-synuclein. Grand Challenges in Parkinson's Disease 2015, Grand Rapids, MI.

Publications

J. Levenson, et al. 2016. NPT088 reduces both amyloid-β and tau pathologies in transgenic mice.


Researchers

  • Kimberley S. Gannon, PhD

    Cambridge, MA United States


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