test tubes with colorful chemicals

A Two-Pronged Approach for SOD1-linked ALS Drug Discovery

By Mel Reichman, Ph.D.

Certain genetic changes in super oxide dismutase-1 (SOD1), the second most common form of inherited ALS, cause this protein composed of two parts (a dimer) to fall apart into individual pieces (monomers). These SOD1 monomers can abnormally clump together in motor neurons during ALS disease. Join me at The ALS Association December webinar to learn about my research to develop new ways to discover novel ALS drugs that stabilize SOD1 dimers. This includes a high-throughput screening technique, which could reveal unexpected, safe combinations of FDA-approved drugs to treat ALS.

Superoxide dismutase-1 (SOD1) is the second most common genetic cause of ALS. Much data over the years indicate that toxicity arises because mutations change the shape of the protein, which somehow turns SOD1 from a beneficial enzyme into a deleterious protein strongly implicated as a cause for ALS.

SOD1 is composed of two identical monomer subunits, called a homodimer. When SOD1 is mutated (called mSOD1), the SOD1 dimers melt into disarranged monomer subunits that form into an amyloid structure. These amyloid proteins misfold into a shape that allows many monomers to stick together forming aggregates, which clog the disposal system of neurons. This describes the amyloid hypothesis for neurodegeneration, which also applies for Alzheimer’s and Parkinson’s diseases.

According to current thinking in amyloid research, the root cause of SOD1-linked familial (inherited) ALS is the greater propensity for mSOD1 dimers (2 subunits) to dissociate into misfolded monomers (1 subunit) that aggregate by a two-step mechanism.

a) The mSOD1 dimers are not stable—they tend to dissociate more readily into two monomer subunits.

b) The mSOD1 monomer subunits misfold, associate with each other abnormally and form clumped-protein amyloid aggregates that are toxic to neurons.

Much published data supports this two-step model of molecular pathogenesis. We hypothesize that a new drug that stabilizes mSOD1 homodimers; i.e., a dissociation-inhibitor drug, will slow disease progression.  The rationale for our research plan draws support from Tafamidis®, the first protein dissociation-inhibitor drug (approved in the EU and Japan) to treat a protein misfolding disorder called familial amyloidal polyneuropathy (FAP).

Our objective is to apply innovative high throughput screening (HTS) assays we developed for measuring SOD1 protein—protein interactions (PPI) to discover dissociation-inhibitor drugs that stabilize mSOD1 homodimers. We believe a drug with this mode of action will reduce misfolded mSOD1 monomer levels, inhibit the formation of neurotoxic amyloid aggregates, and thereby slow disease progression. This research program is in collaboration with Dr. Dave Borchelt at the University of Florida in Gainesville, Florida.

We take a two-pronged HTS approach to discover drugs for treating SOD1-linked ALS. 

Approach 1: Takes the standard long road to identify compounds that stabilize mSOD1 dimers. The expected research milestone is identification of a novel lead suitable for nomination as a preclinical drug development candidate. To this end, we will present data on a potential drug lead we recently discovered that stabilizes mSOD1 homodimers.

Approach 2: To accelerate getting new therapies to the clinic, our other method takes a more unconventional approach, by which we will attempt to identify a combination of two FDA approved drugs that act synergistically to stabilize mSOD1 homodimers.

My webinar will explain this highly innovative technology to discover drugs for treating SOD1-linked ALS and our progress to date for advancing this program.

mel-reichman-head-shot-picture
Mel Reichman, Ph.D.

Webinar details:

Title: ALS: Light from SOD1 Protein-Protein Interactions

Date: Tuesday, December 13, 2016

Time: 4:00 p.m. EST

Speaker: Mel Reichman, Ph.D., Director, LIMR Chemical Genomics Center (LCGC), Senior Investigator, Lankenau Institute for Medical Research (LIMR),

Register Now

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