News from the ALS TDI

by Margaret Wahl on Wed, 2010-09-01 09:39

Topics include new thinking about how ALS develops and progresses, and progress in testing nearly 30 compounds targeting ALS-related pathways

The ALS TDI, an MDA-supported, nonprofit biotechnology organization in Cambridge, Mass., hosted a public webinar (online seminar) on July 27, 2010. Below is a summary of the main points of the report, which is archived on the ALS TDI website.

Many compounds in development

Steven Perrin, CEO and chief scientific officer at the ALS TDI, described the Institute’s drug development pipeline, which includes nearly 30 compounds designed to modulate (alter) the immune system; remodel the nerve-muscle connection (synapse); counteract genetic instructions for a genetic form of ALS caused by mutated SOD1 genes; and combat cellular stress.

The Institute thoroughly tests each of its compounds in carefully controlled trials in mice with an ALS-like disease caused by mutations in the SOD1 gene.

In addition, Perrin said, over the next six to nine months, ALS TDI investigators will be studying upwards of 1,000 mice with TDP43 mutations, which also cause an ALS-like disease, to see how reliable they are as a research tool.

Based on the outcome of those studies, which will cost nearly $1 million, investigators hope to begin testing compounds in the TDP43 mice as well as in the SOD1 mice.

Where does ALS start?

With respect to studying compounds that remodel the nerve-muscle synapse (also called the neuromuscular junction), Perrin said it’s now believed by some experts that ALS may start at the sites where nerve and muscle fibers meet outside the central nervous system, and then spread inward to the motor neurons in the central nervous system (the brain and spinal cord).

Traditionally, the disease has been thought to begin at the motor neurons and spread outward to the neuromuscular junctions.

Nerve fibers, Perrin said, may pull back from muscle fibers over a period of many years before any symptoms develop, during which the body can apparently compensate for the problem.

The late onset of ALS — generally after age 45 — may mean that the body can “remodel synapses adequately” for decades, Perrin said, until it finally loses the ability to do so.

Gene profiling

Perrin described the Institute’s highly advanced capabilities in obtaining and analyzing genome (all genes) expression data from mouse and human tissue samples. Genome expression analysis, or “profiling,” means noting which genes are “turned up” (activated) or “turned down” (deactivated) under particular circumstances. At ALS TDI, investigators are looking at what happens to genes during the ALS disease process or when an experimental treatment is given.

Genome expression analyses are the primary method the ALS TDI uses to decide which pathways to pursue for drug development. For instance, the idea to pursue immunomodulation grew out of genome expression data showing that a number of genes involved in the immune response were overly active in mouse models of ALS and in many humans with the disease.

The Institute is hoping to purchase a new device to make genome expression analyses easier, faster and more cost-effective, Perrin said. The device is made by gene-analysis equipment vendor Affymetrix of Santa Clara, Calif., and is known as the Gene Titan.

“Ten years ago, the ability to do what this machine can do didn’t exist,” Perrin said, noting that the Gene Titan can measure the activity level of any gene in several organisms. “It can profile about 200 samples a week, at significant time and cost savings [over previous methods], and it generates a ton of data,” he said.

Coming up from ALS TDI

ALS TDI’s third-quarter 2010 Research Update webcast and 6th Annual Leadership Summit webcast are slated for 8 a.m. Eastern time, Oct. 5. Visit ALS TDI's website for updated schedules.

Margaret Wahl
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