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Research Update — from ALSA’s National Office
Trial in Inherited ALS Could Be Feasible
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator

A trial that would be designed to show a delay in the onset of inherited amyotrophic lateral sclerosis (ALS) would be feasible but difficult, according to investigators funded by The ALS Association in an article published in the Journal of the Neurological Sciences.

In this article, Michael Benatar, MBChB, MS, DPhil., and colleagues at Emory University in Atlanta, Ga., suggest that such a trial would require prolonged follow-up of patients enrolled. The trial would also require a therapeutic agent that has a robust clinical effect. A therapeutic has yet to be identified.

Benatar is the recipient of the first clinical researcher award funded by the new initiative of The ALS Association, TREAT ALS (Translational Research Advancing Therapy for ALS).

Many previous clinical trials in ALS have followed on a success demonstrated in the most popular lab model of the disease, the SOD1 mouse. Most trials accept patients with ALS that is either inherited or arising spontaneously.

But the mouse most closely mimics inherited ALS, namely, that due to the mutation in the protein, copper-zinc superoxide dismutase (SOD1). The researchers, therefore, propose that a clinical trial be carried out only in people with inherited ALS, and perhaps only with mutations in the SOD1 gene, to realistically obtain the best chance for a successful outcome.

The problem is the rarity of inherited ALS. Yet the investigators have made contact with enough people who are part of SOD1 families to show that a trial might be designed with enough statistical power to show a reliable result.

They are considering a trial that would seek to delay or prevent the onset of the disease. Those in families with inherited ALS can be identified and enrolled before they actually have the disease. Clinical trials in ALS have to date attempted to treat people already affected. A treatment that could be offered before the disease appears would reproduce most closely what can be done in the lab, in animals that model ALS.

Benatar and colleagues note the estimated number of people at risk for developing inherited ALS is much greater (several thousand) than those already diagnosed (under a thousand). This makes the proposed trial more feasible than one that would include only people living with inherited ALS.

The definition of familial ALS is based on the presence of two family members affected by the disease who are related as parent, child, sibling, grandparent, aunt, uncle, niece, nephew, first or second cousin. The investigators’ report includes information about a total of 5,544 people from 116 families. This includes 516 people who have ALS (169 from SOD1 positive families). They also have contacts in place with 1,056 people who are “definitely” or “probably” at risk for inherited ALS, 335 of these from families with a SOD1 mutation.

More than three quarters of responders to the investigators’ requests for information have indicated they would be willing to participate in a clinical trial. These are healthy people who will participate, so the candidate treatment must be very safe, even over an extended period.

Genetic testing, if part of the proposed trial, poses ethical problems. “Certainly, if a future clinical trial design includes the possibility of revealing the results of genetic testing, then it will be necessary to provide appropriate counseling to explain the risks and benefits of obtaining genetic information,” the investigators write in their report.

An accompanying editorial published in the same issue of the journal pointed out some pitfalls in the research plan, notes several benefits of doing a study of at risk familial ALS subjects, and suggests that an international collaboration might capture even more people willing to participate.

The Emory team has advertised for people who think their family carries the disease. There is a toll free phone number-- 888-413-9315--interested parties have to call as researchers cannot legally initiate the contact

For further information about inherited ALS, refer to the report on the FALS Meeting at ALSA National Advocacy Days 2006.