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GAIM a bacteriaphage for clearing amyloids

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, a Phase 1b clinical trial of NPT088 for the treatment of Alzheimer’s disease was launched. This randomized, double-blind, placebo-controlled study had the primary objective to assess the safety and tolerability of multiple doses of NPT088 in patients with mild-to-moderate Alzheimer’s disease. The study evaluated the pharmacokinetics, and exploratory pharmacodynamic characteristics of multiple doses of NPT088, as measured by amyloid-β and tau PET imaging.

On August 15, 2019, the phase 1B study was concluded. While this was not an efficacy trial, the drug did not seem to be efficacious.

The study did not demonstrate an effect of NPT088 to reduce either β-amyloid plaque or tau aggregate burden. With respect to β-amyloid, the failure to translate the animal findings into humans could be due to several factors. One possibility is that small effects were present but undetected due to sample size or other unknown issues. It may also be that the ability of NPT088 to bind β-amyloid plaque in humans differs from that in animal models, and that NPT088 was ineffective as a result, or that exposure to drug was suboptimal.

We await Proclara’s insights into what caused this lack of efficacy and look forward to further information from this company on the future of GAIM.

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

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