A team of researchers in Germany said it has discovered genomic “abnormalities” in a modest percentage of patients with sporadic amyotrophic lateral sclerosis.
If accurate, the team’s findings may bring researchers one small step closer to devising a molecular-diagnostic test for the condition, also known as ALS, or Lou Gehrig’s disease.
But relatively little interest in the disease from government funding agencies and a record of dire outcomes — ALS is almost always fatal — makes it a tough sell for drug or diagnostics makers.
Suddenly, In the Family
It is widely known that roughly 90 percent of ALS cases are sporadic and 10 percent are hereditary. Researchers have also known for some time the existence of genes linked to the familial version of the disease: the copper-zinc superoxide dismutase, or SOD1, gene, found in the q22.1-q22.2 region of chromosome 21, and the ALS2 (alsin) gene, located at the q33 location of chromosome 2 encoding a putative GTPase regulator, are cited the most. Not so the sporadic form, which, despite its preponderance, has only risk factors.
However, results of a study conducted at the Charité University Hospital in Berlin show that sporadic ALS is in fact a multifactorial disease for which modifying genes and environmental agents play key roles in the clinical portrait.
ALS “is, in part, associated with recombination-based rearrangements of genomic sequences,” the authors write in their study, which appears in the April 22 issue of Neurology, the scientific journal of the American Academy of Neurology. “We propose that … chromosome rearrangements [found in the study] may represent a previously unknown genomic risk factor for apparently sporadic ALS.”
The researchers stressed that the results “underscore the need for systemic cytogenetic analysis” of diseases like ALS.
In the study of 85 individuals with sporadic ALS, Charité neurologist Thomas Meyer showed that five people, or nearly 6 percent, had large-scale genomic mutations: three had balanced translocations and two had pericentric inversions. This was enough for Meyer to suggest that these mutations may represent a “previously unknown risk factor” for sporadic ALS — as well as a potential foothold for a diagnostic.
“Since the normal rate of chromosomal abnormalities in ... people is .05 to .1 percent, this is a very high rate for people with ALS,” said Meyer. “It’s very unlikely that these two conditions could appear together that often and not be related.”
To be sure, researchers don’t know how these rearrangements contribute to ALS. “They may result in the disruption or alteration of susceptibility genes that haven’t been identified yet,” Meyer said. “Another possibility could be that an underlying mechanism of ALS that has yet to be determined could promote the development of these chromosomal abnormalities.”
Meyer’s team also tested the patients’ family members for the mutations and found that all but one patient shared the same mutation as their family member. However, the family member “showed no symptoms” of the disease, according to Meyer.
James Allen Heywood, founding director of the ALS Therapy Development Foundation, in Newton, Mass., said “this is a great study. It is very well done.” But he stressed that it “needs further work and confirmation.
“Five of 85 patients does not give you the confidence to go out and do any kind of genetic screen at this point,” said Heywood, who explained that two currently available genetic tests for ALS are responsible for diagnosing 3 percent of all ALS cases in the United States. Heywood said Meyer’s findings “would add to that, but there is a long way to go before you put in any real comprehensive knowledge of the … genes” involved in ALS.
“These are major genetic abnormalities … that you see very rarely,” added Tennore Ramesh, chief scientific officer and director of R&D at the ALS-TDF.
For Jorge Leon, president of diagnostics-consulting firm Leomics, the hurdle is as much financial as it is logistical. He said the markers presented in Meyer’s study “do not … justify a broadly accepted diagnostic or screening test, but suggested it will be possible “in the near future to envision” a microarray-based FISH test that could screen for all associated genetic abnormalities associated with ALS — he said there are more than 20 — for around $350. Leon, a former vice president of functional genomics at Quest Diagnostics, said this would be affordable and practical, assuming it could detect at least half of all inherited cases. Testing for the chromosomal aberrations found in Meyer’s study, by comparison, would cost more than $2,000.
What Price Parity?
ALS itself is somewhat of a poor relation in the world of government funding agencies and the pharmaceutical industry. According to Heywood, though ALS and multiple sclerosis, a similar progressive neurodegenerative disease, have “very similar instances,” MS receives funding from the National Institutes of Health, from the pharmaceutical industry, and at the nonprofit level “literally an order of magnitude higher than ALS — 10 times the funding level. And as a disease, [ALS] ultimately kills the same number of people” as MS.
ALS attacks nerve cells in the brain and the spinal cord. The disease, which is characterized as progressive degeneration of the motor neurons, almost always leads to death. According to the ALS Association, more that 5,000 people in the United States are diagnosed with the disease each year, and as many as 30,000 people in the country are likely to have it at any time.
The majority of individuals with ALS live between two and five years post-diagnosis. Around 20 percent of those with the disease live five years or more, as many as 10 percent will survive more than 10 years, and five percent will live 20 years. More people die from complications of ALS than from Huntington’s disease or MS.
Compounding the poor outcomes is the fact that ALS is notoriously difficult to diagnose. There is no one test, and physicians rely on a battery of common tests — electro-myographies, nerve conduction velocities, high-resolution serum-protein electrophoresis, thyroid and parathyroid hormone levels, and spinal taps — that do little more than rule out other neurodegenerative disorders.
Using genetic mutations as potential diagnostic markers presents its own problems. Because approximately 80 percent of families with familial ALS will not have a change in their SOD1 gene, “a normal SOD1 genetic test is not informative in a family where an SOD1 change has not been identified,” according to Mara Gaudette, a genetic counselor at Northwestern University. “At this time there is no genetic testing to offer non-SOD1 families,” she said. “The determination that an individual has familial ALS is typically based on family history rather than a genetic test.” The efficacy of genetic tests for ALS2 was not immediately clear.
“There’s an across-the-board funding gap that is disappointing because I think ALS probably is one of the most solvable of these [neurodegenerative] diseases, given the quality of its models and the literature, and where it’s at right now,” Heywood told SNPtech Reporter. He said contributing to this funding and research discrepancy is the fact that there are significantly more MS patients than ALS patients alive 25 years after their diagnosis, which means pharmas have a greater incentive to direct their R&D muscle at MS. This phenomenon is evident today in the six drugs approved for the disease. By comparison, there is just one drug on the market for ALS: Rilutek, made by Aventis.
The US Food and Drug Administration, for its part, has taken steps recently to support the therapeutic outlook for ALS. Late last month, the agency recognized ALS as an orphan drug candidate condition, and late last month has even granted orphan-drug status for creatine as a potential treatment for the disease; the drug’s manufacturer, the Avicena Group, said it intends to file an NDA later this year. And last week, the FDA gave the green light to begin studying a trio of other potential ALS treatments.
“What’s ironic is that pharmaceutical companies look at the number of patients for the disease as the market, whereas what is important about that is that with ALS, if you treat it effectively you rapidly will have a very large patient population to [diagnose and] treat,” said Heywood, who will participate in a panel discussion this week at the Massachusetts Biotechnology Council’s 2003 annual meeting. He compared the ALS funding dilemma with diabetes, which, before the advent of insulin, was fatal three years after diagnosis. “Now, [diabetes] is one of the largest patient markets on the planet,” said Heywood.