Featured Article July 29, 2021

Fighting ALS on the genetic level

Cat Lutz, Ph.D., on ALS research at The Jackson Laboratory

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. As of now, there is no known cure, but researchers at The Jackson Laboratory (JAX) and elsewhere are undaunted and hard at work.

One of the main issues with treating ALS is that it's not just one disease. "Much like Alzheimer's Disease, Parkinson's, and other diseases, we're not sure how many specific types of ALS exist genetically," says JAX Professor Rob Burgess, Ph.D.Studies the molecular mechanisms of synapse formation, development and maintenance in peripheral neuromuscular junctions and retina.Rob Burgess , Ph.D. "Is it five different types of disease? 10? 500? They all may look similar, but the differences only emerge when you try to treat the disease at the cause."

Breaking ALS research down on a genetic level

There is functionally no treatment for ALS right now, and Burgess says that if a breakthrough were to come, it would materialize if scientists could identify the genetic variations of ALS and "treat it like a matrix of separate diseases."

The Burgess Lab is helping to identify some of the basic molecular mechanisms in the peripheral neuromuscular junction and the retina. Uncovering more information about the genetics of neuromuscular and neurodevelopmental disorders could yield new treatments for any disease under that umbrella. Their work is finding the "why" and "how" of these neurological genetic disorders, which is essential if researchers can ever unlock how to treat or prevent ALS.

Burgess isn't the only JAX researcher working to solve the ALS puzzle. Associate Professor Greg Cox, Ph.D.Studies the genetics of degenerative muscle diseases using mouse models for SMA, ALS, muscular dystrophy and more.Greg Cox , Ph.D., who works with Burgess on some of the gene isolation work, runs a lab trying to hunt down the molecular pathways underlying degenerative motor neuron diseases in humans, such as spinal muscular atrophy (SMA) and ALS.

The genetics of neurodegenerative diseases

Cox mainly looks at genetic mouse models that develop similar symptoms to ALS and works to identify the genes that may be causing these issues. Isolating the genetic cause of neurodegenerative disease in mouse models can be a painstaking task, and Cox is in a uniquely beneficial place to do it.

"The great thing about JAX is we have a very deep catalog of mice," Cox says. "We can breed the models with specific mutations to target, but we also will have mutations develop by chance in some mice."

These so-called spontaneous mutations are important because if they impact peripheral neuropathy, motor neuron disease, or muscular dystrophy, they may relate in some way to ALS. By researching these genetic mutations, Cox can figure out why they occurred and how the negative symptoms emerged.

"Every gene we isolate and identify has the potential to help a researcher," says Cox, "so we'll keep working through the genes until we get a clearer picture of diseases like SMA and ALS."

Empowering ALS therapeutic research: building 'the factory'

JAX isn't just working on isolating genes associated with ALS. As well as trying to create and improve genetic mouse models for ALS research, Cat Lutz, Ph.D.The primary research goals of the Lutz lab involve developing preclinical mouse models of neurodegeneration to test therapeutics and inform clinical trials.Cat Lutz , Ph.D., Director of the Mouse Repository and the Rare and Orphan Disease Center, also works with major drug companies to evaluate potential therapeutics in-house. The advantage of running therapeutic testing through JAX, Lutz says, is that everything needed is all in one place.

"We built the factory," Lutz says. "We want to provide a universal and standardized test center for therapeutic companies where they can get excellent data quickly and efficiently."

At JAX, scientists can do genetic model-based research much more quickly than they could at their home institution. Lutz says that if a research group tried to run some of these studies independently, obtaining the valuable data could easily take two years. At JAX, that process typically takes just six months. This work has not just delivered vital information about potential therapeutics but significant gains in general knowledge about ALS itself.

"A few years ago, we only had a few gene associations with ALS," Lutz says, "Now that's shot up to well over 20."

Empowering ALS researchers

Since Lutz began working with so many organizations, the ALS mouse models have become more advanced.

"We share all of the models that we create – its standard practice," Lutz says, "It may seem counterintuitive to growing intellectual property, but that's not what we're trying to achieve. This will give patients and researchers the best hope and chance," Lutz says. "This is our policy: sharing everything we have."

Word has gotten out to the ALS research world that JAX is a great place to evaluate new therapeutics. Lutz says big industry players regularly reach out to her, and they don't even need to solicit big grants and contracts anymore.

"We have big companies and groups contacting us," says Lutz, "We have the power to step in and complete whatever part of the research that's needed."

New ALS treatments on the horizon?

When it comes to future therapeutics for ALS, Lutz identified two prospects that she thinks look promising.

The first is targeting a type of inflammation called oxidative stress and damage. Many drugs target this specific type of inflammation, and they are getting better and better. They can delay ALS symptoms and give people more time, but it is not a complete preventative or a "cure."

The second promising development is all about genetics. Some genetic pathways that cause ALS are known to researchers, and drugs have emerged that can knock down or "silence" the mutated or damaged gene that brings about ALS.

"If we can find these pathways and use genetic models to gain insight," says Lutz, "then we may be able to develop treatments that are more effective to more people."

Kuldip Dave, Ph.D., vice president of research at the ALS Association agrees, saying that understanding the genetics of ALS is the best path forward for treatment and prevention.

"We are in the doorway of something big happening," says Dave, "There are over 100 different drug discovery programs active, and the clinical side of the pipeline is very diverse. We have small molecule approaches, gene therapies, stem cell treatments, and all different kinds of modalities being tested."

Genetics research (like the kind going on at JAX) has already unlocked personalized gene therapies that would have been impossible ten years ago. In addition to this, new "platform trials" have enabled researchers to test several treatments in the clinic simultaneously, helping them save valuable time and money.

Three reasons to be optimistic about ALS research

Dave says there is more reason to be optimistic than ever, describing three particular angles of research that he views as having the best chance of helping people affected by ALS.

The first is researching the heterogeneity of ALS. As Burgess said, every form of ALS seems to be different, so how can we mitigate this? According to Dave, it's doing research that does what Burgess has suggested: categorizing and understanding multiple types and sub-types of ALS.

Next is biomarker research. For many diseases (like heart disease), physicians can confidently predict when disease will occur based on specific factors in our health. Right now, there are no early biomarkers for ALS to mitigate damage. "When people are diagnosed with ALS," says Dave, "50% of their neurons have usually already died."

The third angle Dave is watching is assistive technologies. As ALS takes away people's ability to move, speak, and eat, there needs to be ways to help those affected keep their independence and interact with the world in the way they want.

"This is a very complex disease; it's one that we don't even fully understand yet," says Dave. "The best thing is to have a diversified pipeline (of research and therapeutics). In other words, the more shots on goal we have, the more chances we'll have of finding something successful."