$3.1 Million Grant to Help Find Therapies Targeting Neuron Loss in ALS

A $3.1 million grant from the National Institute on Aging (NIA) is intended to help two scientists at Northwestern University find new treatments for amyotrophic lateral sclerosis (ALS).

The grant was awarded to P. Hande Ozdinler, PhD, a professor of neurology at the university’s Feinberg School of Medicine; and Richard B. Silverman, PhD, a professor in the departments of chemistry and molecular biosciences at the Weinberg College of Arts & Sciences.

Silverman’s group developed Lyrica (pregabalin, by Pfizer) a treatment for patients with epilepsy, diabetic nerve pain, spinal cord injury nerve pain, pain after shingles, and fibromyalgia. The scientist previously received funding from the U.S. Department of Defense to screen compounds that may overcome protein clumping in nerve cells — a hallmark of neurodegenerative diseases such as ALS, Alzheimer’s, and Parkinson’s — and then modify them to boost potency.

“The problem we are trying to solve is to identify a common underlying cause for many different neurodegenerative diseases,” Silverman said in a press release. “The compounds we develop initially for ALS may have broader applications for neurodegeneration.”

Silverman and Ozdinler began collaborating to test whether these compounds and their derivatives would have an impact on the progressive loss of upper (brain) motor neurons — specialized cells that control muscle contraction — characteristic of ALS.

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“Our initial results with these compounds are quite promising, and because we use upper motor neurons, our findings will have implications in other upper motor neuron diseases as well,” Ozdinler said. Besides ALS, conditions that damage upper motor neurons include progressive bulbar palsy and spinal muscular atrophy.

Prior work by Ozdinler’s team had reviewed evidence supporting that, besides degeneration of spinal nerve cells, loss of upper motor neurons in the brain’s cortex is also an early event in the disease course of ALS. Also, this study showed that cortical over-activation could be a relevant diagnostic biomarker to enable earlier treatment.

Earlier research had also revealed the key role of the UCHL-1 protein in the survival of upper motor neurons and a viral vector-mediated way to selectively alter gene expression in brain motor nerve cells.

In 2013, Ozdinler and her team were able to make these motor neurons visible in green fluorescence in mice to help find what causes their death and what might protect them.

“We can now track their responses to compounds both in a dish and in the brain,” Ozdinler said. “This was not possible in the drug discovery field before.”