NIH Award Supports Research on Motor Neuron Death


A diverse family of disorders, motor neuron disease is characterized by the progressive weakening and wasting of muscles that ultimately leads to immobility, inability to breathe and death. The disease may progress rapidly over several months or slowly over decades.

Genetic defects cause some forms of motor neuron disease, which affects infants, children and adults, but most cases develop sporadically, triggered by unknown factors. The most common infantile version of motor neuron disease is called spinal muscular atrophy, and the most common adult version is called amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

Despite the differences in their development and progression, researchers believe pathophysiological events are common to all forms of motor neuron disease. However, not enough is known about each variation to construct a unified theory of how motor neuron diseases develop. Researchers hope that insight into one form of motor neuron disease will help them understand and develop therapies for the approximately 5,500 people in the United States who are diagnosed with a motor neuron disease each year.

The effort to better understand motor neuron disease is fortified by a $1.5 million, five-year award to The Children's Hospital of Philadelphia from the National Institutes of Health. The program on motor neuron disease and ALS, led by Robert Kalb, M.D., Division of Neurology, focuses on small proteins called trophic factors that were initially identified for their important role in cell survival. Recent investigations have revealed they play a myriad of roles in neuronal function from learning and memory to provocation of neuron death.

Dr. Kalb's laboratory investigates the cell surface receptors for a particular trophic factor called brain-derived neurotrophic factor, or BDNF. Motor neurons become vulnerable to insult when BDNF binds to and activates a cell surface receptor called TrkB. Many of the insults thought to play a prominent role in motor neuron disease can be stopped by blocking TrkB activation on motor neurons.

Dr. Kalb and his colleagues plan to develop motor neuron protective strategies based on blocking the activation of TrkB by BDNF. Preliminary studies show two classes of drugs, adenosine receptor antagonists and direct tyrosine kinase inhibitors, protect motor neurons from a variety of insults believed to be relevant to motor neuron diseases. Dr. Kalb's laboratory will examine the effects of these agents on TrkB-dependent signaling in cells and study the in vivo pharmacodynamics of these agents as a prelude to application of these agents in ALS models in the future.

This research will attempt to translate basic science observations into new treatments for ALS, with the hope that the development of new drug targets for ALS will guide the way for novel therapies for other, more prevalent, neurodegenerative disorders.