The ALS Therapy Development Institute’s second-quarter Research Update discussed new thinking about how ALS develops and progresses, and described progress in testing nearly 30 compounds targeting various ALS-related pathways.
ALS TDI, an MDA-supported, nonprofit biotechnology organization in Cambridge, Mass., hosted the 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 at Q2 Research Update Webinar. (To see all ALS TDI webinars, go to ALS TDI Webinars.)
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.
Immune system involvement in ALS
In ALS, "we have to finely tune the immune system, not suppress it," Perrin emphasized, when speaking of immune-system modulation efforts.
A compound known as ALS TDI-00846, which blocks a part of the immune system called the "costimulatory pathway," is the furthest along in development. The institute is seeking an industry partner to bring this experimental drug into clinical trials.
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 was 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.
Perrin also 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 the 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.
A ‘rapid-response unit’
Perrin described the mission of the ALS TDI as studying the disease process in ALS; finding or building drugs that alter this process; and doing preclinical (animal) testing of the drugs.
Then, if an experimental compound works in the ALS mice, he said, "our goal is to partner with a suitable pharmaceutical organization," which can bring the drug to clinical (human) trials and ultimately to market. "That's our business model," he said, noting that clinical trials can cost hundreds of millions of dollars to conduct.
"Without effective therapeutic options, the diagnosis of ALS is a crisis," Perrin said. "We think of ourselves as a rapid-response unit for this disease."
About MDA and ALS TDI
MDA and the nonprofit biotech ALS Therapy Development Institute (ALS TDI) of Cambridge, Mass., forged a historic partnership in January 2007 when they launched the largest ALS drug discovery project to date, a three-year, $36 million collaboration to identify biochemical targets in ALS and find drugs that hit them. In January 2010 MDA renewed its partnership with ALS TDI with a grant of $2.5 million.