Today, we are going to be taking a look at GAIM and what it might mean for treating amyloid-based diseases, such as Alzheimer’s, Parkinson’s, and amyloidosis. This approach has the potential to treat multiple age-related diseases at once by targeting a common characteristic that they all share.

Misfolded proteins cause multiple age-related diseases

Proteins are large, complex molecules that regulate almost everything in our bodies, either directly or indirectly. They do the majority of the work in cells and are critical for the function, regulation, and structure of tissues and organs.

Unfortunately, the creation of proteins is not perfect, and sometimes things go wrong; this can lead to the creation of misfolded proteins that are bent out of shape and cannot perform their jobs or, worse, cause harmful behavior in cells by sending the wrong signals.

These misfolded proteins, known as amyloids, accumulate as we age and are thought to cause multiple diseases of aging, including Alzheimer’s disease [1], Parkinson’s [2], and some forms of heart disease [3]. The accumulation of these proteins is known collectively as loss of proteostasis, which is one of the Hallmarks of Aging [4].







A unique approach to misfolded proteins

GAIM (General Amyloid Interaction Motif) has an unusual history. This approach uses a protein from a bacteriophage, a kind of virus that specifically infects bacteria. The M13 bacteriophage was originally discovered and isolated from sewage over fifty years ago. From this humble beginning, it is now being used to develop treatments for multiple diseases.

GAIM is unique, as it uses a viral protein to target the amyloid protein fold, a common feature of amyloids. This viral protein is attached to a fragment of a human antibody: the protein detects the fold and binds to it, and the antibody portion marks the misfolded protein for clearance by the waste disposal systems of the body [5-7].

This therapy appears to target many different amyloids, including amyloid beta, tau, alpha-synuclein, antibody light chain, and transthyretin. With such a wide range of targets, this therapy may have a stronger effect on multiple diseases rather than the more focused approaches of traditional drugs. Essentially, if GAIM works as planned, it could mean that multiple amyloid-based, age-related diseases could be treated at once, effectively targeting a very large portion of this particular aging process.

The history of GAIM







The investigation into GAIM began when Dr. Rajaraman Krishnan and his team discovered the first GAIM molecule in a bacterium [5]. This molecule could bind to Alzheimer’s-causing amyloid beta fibrils (strings of damaged protein), allow dissociation of individual amyloid beta proteins from the fibrils, and force the fibrils to change shape over the course of days without impacting normal proteins.

Three other types of fiber, each made from different forms of damaged protein, were impacted the same way in this experiment, proving GAIM’s wide-ranging effect. Later in the same paper, the natural bacterial form of GAIM was used to create an antibody-based drug, Ig-G3P, as well as another hybrid form. However, Ig-G3P was shown to be the most effective, binding the fibrils effectively and tightly.

Further experiments have shown that GAIM-based therapies have a beneficial impact on neurodegenerative diseases in mice [8], and multiple new antibodies have been developed and tested with positive results [9-12].

NPT088 is the most advanced of the GAIM candidate drugs and is the most tested of the various candidates that are currently in development. A second candidate, NPT189, is following closely behind and is poised to enter human clinical trials in the near future.

The next steps for GAIM







With the first-generation GAIM molecule now in a phase 1b human trial, it still has a long way to go before you might see it in the clinic. Right now, it is being tested on a small group of healthy people in order to establish its safety and identify the correct dose. In the first quarter of 2019, this trial will conclude.

If it’s successful, the drug will move into phase 2 trials in order to test its efficacy and monitor for side effects, with further success leading to a larger phase 3 trial, the goal of which is to look for rare side effects and compare it to the current standard of care, which, for Alzheimer’s disease, is very limited indeed.

However, the need for testing means that this therapy will not be available for at least 4 years, perhaps longer. While there is steady progress being made, drug development and testing is a lengthy and challenging process.

On a positive note, Proclara Biosciences has recently announced the completion of enrolment for its drug’s latest clinical trial, which aims to determine if that drug can cure Alzheimer’s disease.

Conclusion







Currently, there is no effective treatment for Alzheimer’s, Parkinson’s, and similar neurodegenerative diseases. If GAIM-based drugs, which target a core process of aging, are successfully developed, they have the potential to treat multiple neurodegenerative diseases at once, which could completely change how these diseases are approached.

The current candidates have been tested multiple times in mice and have shown a beneficial impact in these studies. While human trials are now in progress, they are still at an early stage, so we should remain optimistic but grounded until more data comes in.

That said, GAIM is a promising technology under development and one that the rejuvenation biotechnology community may wish to keep track of. To help you do this, we have developed the Rejuvenation Roadmap, a curated database showing the current status of therapies in development.

References

[1] Bloom, G. S. (2014). Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology, 71(4), 505-508.







[2] Irwin, D. J., Lee, V. M. Y., & Trojanowski, J. Q. (2013). Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nature Reviews Neuroscience, 14(9), 626.

[3] Ruberg, F. L., & Berk, J. L. (2012). Transthyretin (TTR) cardiac amyloidosis. Circulation, 126(10), 1286-1300.

[4] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[5] Krishnan, R., Tsubery, H., Proschitsky, M. Y., Asp, E., Lulu, M., Gilead, S., … & Kirschner, D. A. (2014). A bacteriophage capsid protein provides a general amyloid interaction motif (GAIM) that binds and remodels misfolded protein assemblies. Journal of molecular biology, 426(13), 2500-2519.

[6] Oddo, S. (2008). The ubiquitin‐proteasome system in Alzheimer’s disease. Journal of cellular and molecular medicine, 12(2), 363-373.







[7] Ciechanover, A., & Kwon, Y. T. (2015). Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Experimental & molecular medicine, 47(3), e147.

[8] Levenson, J. M., Schroeter, S., Carroll, J. C., Cullen, V., Asp, E., Proschitsky, M., … & Shoaga, S. (2016). NPT088 reduces both amyloid-β and tau pathologies in transgenic mice. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 2(3), 141-155.

[9] Krishnan, R., Asp, E., Proschitsky, M., Lulu, M., Chung, C., Rockwell-Postel, C., … & Wright, J. S. (2017). MUTAGENESIS OF THE GENERAL AMYLOID INTERACTION MOTIF (GAIM) REVEALS A STRUCTURE-ACTIVITY RELATIONSHIP FOR MISFOLDED BETA-AMYLOID AND TAU AGGREGATES. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 13(7), P1006-P1007.

[10] Chung, C. et al (2017), General amyloid interaction motif (GAIM) reduces misfolded alpha synuclein inclusion formation in cell-to-cell transmission.

[11] Asp, E. et al (2017), Selection of General Amyloid Interaction Motif (GAIM)-Ig–fusions with increased targeting activity for misfolded beta amyloid and tau.







[12] Proschitsky, M. et al (2018), GAIM Fusions are Therapeutic Candidates for Peripheral Amyloidosis.