A Long and Winding Road

by Margaret Wahl on Thu, 2008-05-01 17:00

The year in research

The road to ALS treatment development has been long and hard. But MDA, along with the National Institutes of Health (NIH) and pharmaceutical companies, is finding there are more frequent signposts.

Among the most interesting developments of this year is the finding in a 44-person study in Italy that lithium carbonate, used to treat bipolar disorder, may have slowed the course of ALS when combined with riluzole.

Sixteen trial participants were randomly selected to receive riluzole plus two daily doses of lithium, while the remaining 28 were randomly assigned to receive riluzole only. After 15 months, about a third of those who took riluzole alone had died; all those taking riluzole and lithium had survived. The disease had progressed markedly in the riluzole-only group, but very slowly in the riluzole-plus-lithium group. An MDA-supported trial of lithium designed to test these findings is on the drawing board.

Also of note are two 2007 studies of all the DNA of a group of people with sporadic (noninherited) ALS and all the DNA of a group of people without the disease (“whole-genome association” studies). One, which had MDA support, showed at least one statistically significant difference, in a gene whose function so far is unclear. The other, which had NIH support, found no significant differences.

Scientists have concluded that, whatever the causes of ALS may be, they’re highly unlikely to include a clear genetic “smoking gun” and are more likely to reflect a combination of genetic variants and other factors.

In January, a Mayo Clinic and University of Miami study employed a narrower approach to a genome association analysis, examining only genes involved in various pathways, such as “axon guidance,” the development and maintenance of nervous-system “wiring.” When 128 of these genes were compared in people with and without ALS, the differences were significant.

Since the finding that Gulf War veterans have a higher than average rate of ALS, new research has implicated exposures to organophosphate pesticides and drugs that were given to military personnel to protect them from nerve gas attacks.

Evidence first pointed to a combination of such exposures and genetic variations in a gene for a detoxifying enzyme called PON, because people with ALS are more likely to have a particular PON variant than are unaffected people. However, a more recent finding has shifted attention to variations in a gene for a different enzyme, NTE, as a possible contributor to ALS when combined with toxic exposures.

Also this year, the MDA-supported ALS Therapy Development Institute in Cambridge, Mass., has focused on “gene expression” studies to help understand the ALS disease process. Gene expression refers to how active a gene is (how much protein is being made from its instructions).

The Institute, funded through MDA’s Augie’s Quest, is now analyzing data from a gene expression “profile” in ALS-affected mice and is starting to put together a profile for ALS-affected humans using tissue samples.

ALS TDI investigators also have uncovered variations in ALS-affected mice that may explain why drugs that showed promise in these mice frequently failed when tested in people.

These so-called SOD1 mutant mice have multiple copies of mutated SOD1 genes, which cause about 1 percent to 3 percent of human ALS cases.

The investigators found, for example, that the number of mutated gene copies, which has a profound effect on the severity of the disease, varies among these mice. Especially in experiments with small numbers of mice, the chance occurrence of an excess of low-copy-number mice in the treated group and of high-copy number mice in the untreated group could make it appear that a useless drug has a positive effect.

ALS Drug Development
Strategy Drug Status of Research

Boost transport of potentially toxic nervous-system compound glutamate away from nerve cells ceftriaxone (Rocephin) Clinical trial under way
Block molecular landing sites (receptors) for glutamate talampanel Clinical trial in planning stage
Improve cells’ defenses in adverse conditions by stimulating production of molecular “chaperones” arimoclomol Shown to be safe and well tolerated;
however, FDA* has placed phase 2b trial
on hold while it further analyzes rat
Interrupt cell death pathway; control inflammation minocycline Shown to hasten functional losses in ALS in a phase 3 trial
Prevent cell death sodium phenylbutyrate Shown to be safe and tolerated by majority of trial participants
Block synthesis of SOD1 protein in patients with SOD1-related ALS SOD1 antisense compound Undergoing toxicity testing in animals; clinical trial in planning stage
Administer a neurotrophic (nervenourishing) protein IGF1 (Myotrophin) Third phase- 3 trial has been completed; results not yet available
Reduce levels of TNF-alpha, a protein involved in inflammation thalidomide (Thalomid) Phase 2 study completed; results not yet available
Alter immune system glatiramer acetate (Copaxone) Phase 2 trial showed it was safe but not effective
Support cells’ energy metabolism and neutralize toxic free radicals coenzyme Q10 Clinical trial of high-dose coQ10 showed no benefit
Confirm or refute findings in small clinical trial; possibly, support cells’ ability to dispose of toxic molecules lithium carbonate Clinical trial in Italy showed delayed progression of ALS, planning for new trial under way
*FDA = U.S. Food and Drug Administration

Current experiments at the ALS TDI are using mice with standardized gene copy numbers to minimize misleading results.

“This year of ALS research has had its successes and disappointments,” said Sharon Hesterlee, MDA’s Vice President of Translational Research. “But I think we’ve uncovered some fundamental new directions to pursue, particularly with respect to narrowing the search for ALS-related genetic differences and in ensuring that mouse studies are as predictive of clinical trial outcomes as they can possibly be.


Genetic and Other Risk Factors in ALS
Objective Study Status of Research

Identify genetic factors that increase risk for or influence course of ALS

NIH*-based whole-genome association study (April 2007)

TGen** whole-genome association study (August 2007)

Mayo Clinic and University of Miami study (January 2008)

NIH*-based followup study

Found no significant differences in ALS vs non-ALS DNA

Found one significant difference in ALS vs non-ALS DNA

Found difference in ALS vs non-
ALS DNA in axon guidance genes

under way

Study relationships among genetic makeup, environmental exposures and ALS Genetic and environmental epidemiology study in ALS based at Columbia University ongoing
  Genetic and environmental risk factors study based at Massachusetts General Hospital and Northwestern University ongoing
Studies of role of TDP-43 gene and protein in ALS four recent studies this year, one describing TDP-43-containing clusters in non-SOD1-related ALS; three showing mutations in gene for TDP-43 can cause ALS ongoing
Study disease course, quality of life; provide leads for research and improvement of care ALS Connection Registry (www.alsconnection.com) ongoing
Track patterns of ALS among those who served in U.S. military Veterans With ALS Registry (www.durham.hsrd.research.


Previous studies showed elevated risk of ALS in U.S. military veterans in general, and in Gulf War veterans; new study shows Vietnam service linked to shortened survival with ALS

Large-scale review of medical records to look for patterns in ALS CDC*** ALS surveillance project ongoing
Determine whether retroviruses play a role in ALS Search for evidence of retroviral involvement in ALS A virus called XMRV has been ruled out, but others are being studied.
*NIH = U.S. National Institutes of Health
**TGen = Translational Genomics Research Institute
***CDC = U.S. Centers for Disease Control and Prevention
Margaret Wahl
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