Campus Alert: Find the latest UMMS campus news and resources at umassmed.edu/coronavirus

Page Menu

About ALS

Development of Therapeutic Treatments for ALS

Amyotrophic lateral sclerosis (ALS) is an incurable disease. It results from the progressive loss of motor neurons, those that control voluntary movement, and ends in paralysis and eventual death by respiratory failure. Although ALS is considered an orphan disease, it is estimated that more than 500,000 individuals now alive in the U.S. will develop this disease.  Most people who develop ALS are between the ages of 40 and 70 at the time of diagnosis with an average age of 55. Nearly 50% of patients die within 3 years and 75% within 5 years. Currently, riluzole, the only therapeutic treatment for ALS patients, and approved over 20 years ago, results in a minimal survival increase of only 3-6 months.

I have been working in the field of genetics for over 20 years, and began my focus on ALS just 12 years ago. In this short period of time, my laboratory has established itself as a leader in the field.

  • We’ve successfully identified novel ALS genes: FUS in 2009; PFN1 in 2012; and TUBA4A in 2014.
  • We’ve published our discoveries in high profile peer-reviewed scientific journals: Science; Nature; Neuron.
  • Significantly, it was our leadership in a multi-national collaboration of 60 researchers across 8 countries and 28 institutions that led to the identification of the TUBA4A gene.

Based on my expertise in ALS genetics, the organizers of Project MinE approached me in 2013 to become their Director in the USA. Project MinE is an organization that originated in the Netherlands whose objective was to sequence the genomes of 15,000 ALS patients and 7,500 control samples. I accepted and in early 2014, together with my co-Director Dr. Jonathan Glass, Director of the Emory ALS Center, we approached the ALS Association (ALSA), the largest charitable organization for ALS research, seeking funds to establish Project MinE USA. ALSA was very enthusiastic but lacked the financial resources to support us. However, in the summer of 2014, the Ice Bucket Challenge, a social media phenomenon, took the world by storm and forever changed the face of ALS.

In 2012, Pete Frates, a former captain of the Boston College baseball team, was diagnosed at the age of 27. Rather than allowing the disease to simply take its course, Pete, along with his family and friends, decided to make a change and concentrate their energy on raising money for ALS research together with ALSA. From their efforts, the Ice Bucket Challenge was created and soon went viral and become a worldwide sensation. The Ice Bucket Challenge was not only instrumental in raising money for ALS research, it also raised awareness for a disease that was known by few people before 2014.

As a result of the extraordinary funds raised by the Ice Bucket Challenge, ALSA returned to us and funded our work for Project MinE USA with a $1M donation. With this award, we were able to continue our goal of identifying previously unknown genes for ALS. In July 2016, at the two-year anniversary of the Ice Bucket Challenge, we announced the identification of another new ALS gene, NEK1. Again, I led the study for this gene that included over 80 researchers across 11 countries and nearly 40 institutions. The discovery garnered worldwide media attention proving the strength of global collaborations and demonstrating the impact of many individual contributions. It has been reported by all major television media outlets (CBS, ABC, NBC, FOX, CNN, PBS), print/web agencies (USA Today, Wall Street Journal, Washington Post, Scientific American) and world news agencies (Thomson Reuters, BBC, Al Jazeera). The story was even reported as “trending” on Yahoo, Reddit, and Facebook. I had the pleasure of conducting interviews for several of these agencies.

Why is it important to identify novel ALS genes? One benefit is that it opens up new avenues of research. For instance:

  • The identification of some genes, leads to new diagnostic tests or eventually gene therapy for a small set of ALS cases.
  • The discovery of new ALS genes leads to the essential and much needed development of model organisms, such as mice that develop ALS when the mutant gene is introduced, providing opportunities to understand the disease that would not be possible otherwise.

However, the prime value of identifying new genes is that it lets us identify the molecular components, pathways and processes that become defective in ALS patients. Targeting such pathways will make it possible to develop new therapeutics for all ALS patients, not just those with a mutation in a specific gene. For instance, our previous discoveries of the ALS genes PFN1 and TUBA4A gave us information suggesting that both genes are involved in the structure and maintenance of the cytoskeleton (described below). Our latest discovery of NEK1, another cytoskeleton-related gene, further solidified our belief that the cytoskeleton plays a vital role in the neuronal degeneration observed in all ALS patients. The information gained from our genetic studies may very well lead to a therapeutic treatment for ALS patients.

The cytoskeleton is a vital component to all cells but especially neurons. Just like the skeleton for your body, the cytoskeleton (“cyto” meaning cell) does the same for all cells in your body. Unlike our body’s skeleton, the cytoskeleton plays an important role in transporting cargo (which can be protein, cellular vesicles and RNA) from one part of the cell to another. This transport process is known as axonal transport and is known to be disturbed in ALS patients. The cytoskeleton works by providing the “rails”, similar to railroad tracks, in which the cargo can be transported. Also comparable to railroad tracks, defects in the cytoskeleton (or railroad tracks) will block the transport of this cargo. This is especially important in motor neurons, where the axons can be as long as three feet long. Cytoskeletal defects can also be visualized in the neurons of nearly all ALS patients.

Over the past few years, my laboratory has focused on identifying potential therapeutics that can alleviate the cytoskeletal defects observed in ALS patients. We led a multi-institutional effort to identify such therapeutics with groups from University of California San Francisco, Brandeis University and other members of UMass Medical School. Our concept is relatively simple. We had shown that if you place a mutant ALS gene into healthy neurons, they die in typically one week. As such, we can test a library of different “compounds” to identify those that prevent the neurons from dying. Such “hits” can then be tested in additional cellular and animal models of ALS. Although our budget was very limited and allowed screening of only ~220 “compounds”, the assay identified one compound that could rescue dying neurons harbouring any of three different mutant ALS genes. We are currently testing this compound in additional cellular and animal models of ALS.

It is truly my belief that through our continued efforts, we can identify one of the first true therapeutics for ALS patients in over 20 years. It is my full intent to expand our ability to screen for compounds that can rescue dying neurons resulting from mutant ALS genes altering the cytoskeleton. We intend to expand our screening capacity beyond a few hundred compounds to tens of thousands. Furthermore, we intend to establish high-throughput approaches to quickly test our hits in numerous cellular and animal models.

Unfortunately, as I am sure you aware, scientific research is expensive. To accomplish these goals and convert our genetic findings into patient therapeutics requires money. We are actively seeking funds through government grants and charitable foundations; however, funds from these sources can be difficult to obtain, require great lengths of time to acquire and are limited in their amounts available.

I am asking for donations to support our work and allow it to continue. Our primary goal is a direct therapeutic for all ALS patients. My track record proves our distinctive capabilities to reach our goal and the strengths of collaborations with all members of the ALS scientific community to expedite this work.