Actin Against ALS

Highlights

• Amyotrophic lateral sclerosis (ALS) is a devastating disease that progressively robs people of the ability to do the simplest yet most precious acts of daily living.
• ALS has no survivors, no effective treatments, and no cure.
• At a cellular level, all forms of ALS include disruptions in the actin-based cytoskeleton of motor neurons.
• Our novel approach is to normalize these cytoskeletal disruptions by developing therapeutic small molecules capable of restoring function in ALS-afflicted motor neurons.
• Recipient of $100,000 PInCh Award + $15,000 Bonus Award for Engineering Good Health.

Problem

ALS is a devastating, progressive condition with an average life expectancy of 2-5 years from diagnosis. ALS is characterized by the degeneration and death of motor neurons, which are responsible for controlling voluntary muscle movement. When these cells die, affected individuals are unable to perform basic functions of life including eating and breathing.

There are currently no effective ways to treat, reverse, or cure ALS. Unlike other diseases, ALS has no survivors; every 90 minutes someone is diagnosed and every 90 minutes someone dies as a result of ALS. It has an incidence of 1.5 cases per 100,000 and a prevalence of 5.2 per 100,000 in the United States. ALS knows no racial, ethnic, or socioeconomic boundaries. While there are slight disparities for gender (males more commonly affected than women), age (persons aged 60-79 years are most commonly affected), and occupation (military personnel are over twice as likely to be diagnosed), ALS can affect anyone at any age, and it is always fatal.

Care for people living with ALS is largely supportive, addressing symptoms and providing assistance in the form of feeding tubes, speech-generating devices, and power wheelchairs. For a person affected by ALS, the financial burden is estimated at about $300,000 each year.

Solution

Although a clear understanding of the mechanisms underlying motor neuron cell death in ALS is lacking, all people with ALS experience a similar set of symptoms and their motor neurons are affected by similar cellular processes. With this in mind, our team has focused on ALS linked to mutations in proteins associated with the actin cytoskeleton of motor neurons.

The cytoskeleton is a complex highway system used for transporting things inside a cell, and dysfunction of this highway system underlies all forms of ALS. Our approach is to test the ability of novel small molecule compounds developed by our laboratory to normalize the actin cytoskeleton. We will also work to optimize these small molecules to increase their ability to reverse cytoskeletal and other pathological changes in motor neurons harboring ALS-linked mutations.

These studies will establish a novel, paradigm-shifting conceptual platform for ALS therapeutics that preserve function of motor neurons, slow disease progression, and reverse the disease process. This work also has broad implications for other neurodegenerative conditions, including Alzheimer’s and Huntingdon’s Diseases.

Team

• Christi Kolarcik, PhD (University of Pittsburgh School of Medicine) is an Assistant Professor in the Department of Pathology and a neurobiologist by training. She has research expertise in the motor system and ALS.
• Partha Roy, PhD (University of Pittsburgh Swanson School of Engineering) is a Professor in the Department of Bioengineering with a long-standing track-record of research on the actin cytoskeleton and diseases associated with cytoskeletal dysfunction.
• Our team includes the expertise of clinicians that specialize in ALS as well as collaborators in Pitt’s Department of Neurobiology and at the Center for Biologic Imaging.
• We are also closely tied to the people we wish to serve with these novel therapies, having people living with ALS and their loved ones as advisors to our research team.

Path to Impact Plan

With PInCh support, we will validate our paradigm-shifting therapeutic approach in benchtop and preclinical studies. Our goal is to identify a lead compound (or compounds) to take to clinical trials in partnership with an outside funder or industry partner. We expect that this therapy would not only prevent disease progression but provide the opportunity for damaged cells to undergo reparative processes.

While our plan is to target people with ALS affected by specific genetic mutations, cytoskeletal issues underlie 100% of ALS cases as well as many other neurodegenerative diseases. Therefore, we can expand our impact by manipulating our lead compound to create a platform technology for conditions that include Alzheimer’s and Huntingdon’s Diseases as well. We also anticipate that data generated with PInCh support will enable us to be competitive for larger scale grant applications to the National Institutes of Health and the Department of Defense.

Frequently Asked Questions

• Who will benefit from this therapy? The pathological features targeted by these novel small molecules are shared with all ALS cases. Moreover, similar pathophysiology is observed in other neurological disorders including Alzheimer’s and Huntingdon’s Diseases. Our overall strategy will benefit each of these populations with the potential to prevent/slow disease progression and reverse neuronal damage.
• How will $100,000 make an impact? PInCh support will enable us to validate our novel approach and to develop a lead compound or compounds to move toward clinical trials. It is a critical first step to getting this therapy to the people affected by ALS.