ALS Research Update | October 2019

ALS Research Update, October 2019

Welcome to the October 2019 ALS Research update. This month, you’ll learn about the progress researchers have made in: transforming the way clinical trials are conducted; understanding the roles that the microbiome and protein clumping may play in ALS; and identifying the mechanisms by which different genes may contribute to disease.

Does the gut microbiome play a role in the progression of ALS?

A recent study suggests that a specific substance, produced by bacteria naturally found in our guts, can slow the progression of ALS in mice.

The gut microbiome is the natural collection of microorganisms (bacteria, viruses, fungi, etc.) that live in our gastrointestinal tract. The gut microbiome plays an important role in nutrient and mineral absorption, as well as overall gut health. Recently, however, increasing evidence suggests that the gut microbiome can also play a role in one’s susceptibility to diseases, including those of the brain.

In a study recently published in the journal Nature, a mouse model that mimics ALS was given broad-spectrum antibiotics in order to better understand the effects of wiping out a large portion of the gut microbiome. The results showed that treatment with antibiotics made disease symptoms worse.

Using advanced computational methods, the researchers then compared the composition of the gut microbiome of ALS prone mice to that of healthy mice. They found that 11 different bacterial strains may play a role in the progression of ALS. To test their effects individually, these bacterial strains were given back one by one to the ALS mice previously treated with antibiotics. They found that one bacterial strain, called Akkermansia muciniphila (AM), significantly slowed disease progression and prolonged survival in the mice.

This work is an exciting step in identifying how environmental factors may influence the progression of ALS. The researchers recognize, however, that this study is preliminary and that larger, future studies are required to increase our understanding of the potential impact of the microbiome on human ALS and how it may be harnessed to develop new therapeutic options.

Insights into a molecular highway within motor neurons that may be disrupted in ALS

Researchers have identified a key role for the ALS-linked protein ANXA11 in RNA transport within motor neurons.

This role links together several important pathways in our understanding of ALS and represents an important step forward in our ability to identify new targets for treatment options.

Motor neurons are the long living wires within our bodies that carry the signals from our brain to our muscles, allowing us to move. Motor neurons can be required to carry signals for far distances and can be very long, with some measuring up to 1 metre in length.

Due to the size and shape of motor neurons, efficient transport of substances within the cell, such as RNA, is very important to maintain good health. RNA carries genetic information that is copied from DNA, which is found in the nucleus within the cell body. Since RNA directs the formation of proteins, and protein formation is required in all parts of the cell (even at the tip of the axon, see illustration), RNA must travel long distances to where it is needed. How RNA is transported to these far regions is currently not well understood.

In a new study published in the journal Cell, a team of researchers found that ANXA11 may play an important role in tethering RNA to structures that can transport it to distant sites in the motor neuron. The researchers describe the RNA “hitchhiking” onto other moving structures within the cell. Mutations in ANXA11 linked to ALS are thought to impair its ability to tie RNA to these moving structures. Funded in part through an ALS Canada–Brain Canada Arthur J. Hudson Translational Team Grant, this study identifies a critical cellular function that may be disrupted in ALS.

Researchers identify a new gene that may be a therapeutic target in C9ORF72-linked ALS

A new study suggests that a specific gene, RPS25, may be a key player in the toxicity associated with ALS-linked C9ORF72 mutations.

Within cells, these mutations lead to the production of destructive proteins called DPRs. These DPR proteins tend to clump together in cells and accumulate within the central nervous system of patients with C9ORF72-linked ALS.

The study published in the journal Nature Neuroscience, explains how researchers set out to identify genes that may be able to regulate the production of DPRs within cells. They first scanned all of the genes in yeast cells and identified 42 that were able to either increase or decrease DPR levels. They found that by reducing one gene in particular, called RPS25, they were able to decrease the level of these toxic proteins in yeast cells by 50%.

To determine if the results from the yeast cells could be translated into humans, the researchers then explored the effects of the RPS25 gene in motor neurons derived from ALS patient stem cells. Again, the researchers found that blocking RPS25 in human cells lead to a decrease in total DPR levels and an increase in cell survival. To further validate the role of RPS25 in ALS, the researchers also utilized an ALS fruit fly model and found that reducing the amount of RPS25 increased the lifespan of the fly.

This work provides a deeper understanding of how toxic DPR proteins are made in cells and potentially how researchers can hinder that process. The next step is to test these findings in other animal models. The researchers noted that it is important to determine whether more complex animals, such as mice or rats, can survive without the RPS25 gene since it could have many additional and possibly important functions within a cell.

A revolutionary new way to conduct clinical trials in ALS

The Sean M. Healey & AMG Center for ALS (the Healey Center) at Massachusetts General Hospital will launch the first ever platform clinical trial in ALS.

The Healey Center will launch the platform trial at 54 sites across the U.S. with three therapies to start, followed by adding two more shortly afterwards. The investigators are excited about this new approach as they believe the ability to test multiple drugs at one time will move the global field more quickly toward the goal of finding a treatment for ALS.

A platform trial is a clinical trial where multiple treatments are tested and evaluated at the same time. Platfrom trials help to accelerate drug development by allowing investigators to test more drugs, increase patient access to trials and reduce costs. A previous study that focused on efficiences of platform clinical trials showed that the platform model could help scientists find beneficial treatments using fewer patients, in less time and with a greater probability of success. New treatments can be added to a platform trial as they become available and since the placebo group for each study involved can be shared, participants will have a greater chance of receiving an active drug over a placebo.

Prior to initiating the HEALEY ALS Platform Trial, the Healey Center issued a worldwide call for the best therapeutic ideas and received 30 applications from 10 countries. A panel of expert ALS scientists reviewed the applications and selected the top five that were ready to enter the platform trial. The experimental treatments include CNM-Au8 (Clene Nanomedicine), IC14 (Implicit Bioscience), Pridopidine (Prilenia), Verdiperstat (Biohaven Pharmaceuticals), and Zilucoplan (Ra Pharmaceuticals).

Study suggests that clumping of TDP-43 commonly observed in ALS may be protective to cells

Researchers have long debated whether protein clumps found within cells in many neurodegenerative disorders are toxic or protective. New ALS research suggests it may be the latter.

Proteins clumping together within cells is a hallmark feature of many neurodegenerative diseases. For example, clumps of a protein called TDP-43 are found in nearly all cases of ALS. Recently, scientists have found that that these proteins can also gather into a liquid-like state before clumping. Which is the most toxic form is still up for debate.

In a new study that appeared in the journal Nature Communications, researchers set out to identify what form of TDP-43 causes cellular toxicity. They created more than 50,000 different abnormal forms of TDP-43 by changing one or two amino acids (the building blocks of proteins) at time and analyzed their toxicity in yeast cells. The researchers felt that by studying all possible forms of the protein they would have a much more reliable understanding of its behavior.

Interestingly, they found changes that promoted the clumping of TDP-43 were actually less toxic in the yeast model. On the other hand, changes that promoted TDP-43 to be more liquid-like, increased toxicity. This led the researchers to conclude that the clumping of TDP-43 is not harmful to cells and instead may be a protective mechanism by pulling proteins away from a more toxic form and into the clumps.

It is important for the researchers to validate these findings in human motor neurons in order to confirm a protective effect in cells more closely linked to human disease. If confirmed, this may drastically change how ALS and other neurodegenerative disease are treated in the future since to date many therapies have aimed to reduce what we now know may be protective clumps.