Harvard Stem Cell Institute scientists offer new hope for the 30,000 Americans living with a paralyzing and fatal disease with no known cause.

New York Yankee first baseman Lou Gehrig was having a lousy season in 1939. Known for his record-number home runs and perfect game attendance, the so-called “Iron Horse” was suddenly having trouble keeping his balance and catching fly balls. Gehrig was soon diagnosed with a rare, late-onset, and fatal disease that would come to take his name.

Lou Gehrig’s disease, more formally known as Amyotrophic Lateral Sclerosis (ALS), is a neurodegenerative condition that involves the breakdown of motor neurons in the brain and spinal cord. People with ALS may experience weakness in their limbs followed by a rapid and progressive paralysis that leads to respiratory failure. Every year, over 5,000 Americans are diagnosed with ALS, which primarily affects people in their forties through seventies. The cause of ALS is largely unknown and there is currently no effective therapy.

A Complex Disease

Several factors contribute to the difficulty in finding effective therapies for ALS. Ninety percent of cases are sporadic, which means they are caused by a combination of genetic mutations and/or presumed environmental variables. Only ten percent of ALS cases are caused by inherited forms of known genes. This diversity of potential causes means that any therapy would only be effective on a certain subset of patients. Furthermore, until recently, there was also no way to test if a drug would even work on motor neurons, the cells affected in ALS, because they couldn’t be obtained in large numbers.

Cellular Insights

Harvard Stem Cell Institute (HSCI) scientists are leaders in the search for an effective therapy for ALS. The accelerated pace of advancements in stem cell biology at HSCI has enabled the production of millions of motor neurons generated from mouse embryonic stem cells derived from ALS genetic disease models, as well as normal human embryonic stem cells.

In a leap forward for the field, HSCI scientists have also derived human induced pluripotent stem cells — mature cells that are manipulated back to a stem cell state — from the skin and blood of ALS patients. This achievement means that the disease can be studied in a laboratory culture dish filled with the cells responsible for this devastating condition, allowing HSCI scientists to identify new therapies for ALS.

Human motor neurons derived from ALS patients have been used by HSCI Principal Faculty member Kevin Eggan, PhD, to glean new insights into the development and progression of the disease. His group found a toxic signal produced by accessory neuronal cells — called glial cells — that compromises the survival of motor neurons in patients with ALS, a previously unappreciated characteristic of the disease.

A New Model of Drug Discovery

In addition, HSCI’s investment in the Therapeutic Screening Center has made it possible to screen several drug candidates for ALS. HSCI Executive Committee member Lee Rubin, PhD, has identified two small molecules and their target signaling pathways that promote survival of human ALS patient-derived motor neurons. Together, members of the Rubin and Eggan labs have pioneered a method to profile these candidate compounds, as well as prior clinical candidates, against a panel of sixty motor neuron populations derived from individual ALS patient and control skin cells. Through this so-called “in vitro clinical trial,” these HSCI scientists expect that they will be able to identify those compounds that work on the largest numbers of patients as well as identify those subsets of patients that respond best to selected drug candidates.

Preliminary data on the compounds profiled by the Rubin and Eggan labs are consistent with the known effectiveness of current ALS therapies, and further suggest that the two HSCI candidate compounds are highly active in comparison. If this test proves to be a model of drug development and is truly predictive of clinical response, it will have profound implications for dramatically increasing the efficiency with which effective therapies for complex diseases are discovered and developed, thus extending the implications of this work well beyond ALS.