Proclara – GAIM

Summary

Proclara Biosciences is developing the General Amyloid Interaction Motif (GAIM), a broad tool that the company hopes will disrupt existing amyloid aggregates and halt their spread. GAIM has been in development for a number of years thanks in part to support from the Michael J Fox Foundation.

Amyloids are responsible for multiple crippling and fatal age-related diseases, including Alzheimer’s, Parkinson’s, antibody light chain (AL) amyloidosis, and transthyretin (TTR) amyloidosis. Their aggregation represents a failure of proteostasis, the body’s ability to process, create, and recycle proteins in a healthy way.

There are many kinds of amyloids, including amyloid-β (Aβ), tau, and a-synuclein aggregates, which accumulate in the brain to cause Alzheimer’s and Parkinson’s disease, and antibody light chain and transthyretin aggregates, which accumulate in the peripheral organs, causing systemic amyloidosis to develop.

Proclara has opted for a novel approach: it focuses on the amyloid protein fold, which is the one common thing all these aggregates share. This fold is present in all of the problematic amyloids, so it represents a unique target for a GAIM-based therapy.

Proclara hopes to use GAIM to directly affect the characteristic folds common to all amyloids in order to destroy these harmful aggregates and prevent more from forming. Its approach has the potential to treat all types of amyloids and, if successful, could prove to be the solution to diseases that have, until now, remained incurable. NPT088 is their first candidate therapy and they are following that up with a more refined version called NPT189.

In July 2018 Proclara announced that it has completed enrollment in its ongoing Phase 1b clinical trial of NPT088 for the treatment of Alzheimer’s disease. This randomized, double-blind, placebo-controlled study is designed to evaluate the safety and tolerability of NPT088 and its effect on Alzheimer’s disease pathology as assessed by amyloid-β and tau PET imaging in patients with mild-to-moderate Alzheimer’s disease. The company anticipates that study data will be available for NPT088 in first quarter 2019.

References

[1] Asp, E et al, Selection of General Amyloid Interaction Motif (GAIM)-Ig-fusions With Increased Targeting Activity for Misfolded Beta-Amyloid and Tau (2017).

[2] Chung, C. et al, General Amyloid Interaction Motif (GAIM) Reduces Misfolded Alpha-Synuclein Inclusions Formation in Cell-to-Cell Transmission Model (2017).

[3] Krishnan, R et al., Mutagenesis of the General Amyloid Interaction Motif (GAIM) Reveals a Structure-Activity Relationship for Misfolded Beta-amyloid and Tau Aggregates (2017).

[4] Levenson, J et al., NPT088 reduces both amyloid-β and tau pathologies in transgenic mice, Alzheimers Dement (2016).

[5] Krishnan, R et al., A bacteriophage capsid protein provides a general amyloid interaction motif (GAIM) that binds and remodels misfolded protein assemblies, J Mol Biol (2014).

Website: Proclara Biosciences