Clinical Research

1. New Drug Development in ALS

The University of Miami ALS Clinical Trials Division is one of an international group of Centers involved in trials to develop new drugs to treat ALS.

Nerve growth factors are proteins present in the normal nervous system that play a major role in the development of the embryonic nervous system, and may play a role in nervous system regeneration. It is believed that they might be able to slow down the rate of degeneration or improve the rate of repair in such diseases as ALS. They have been shown to do so in animal models of ALS.

We have been involved in trials of ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF). CNTF and GDNF did not improve ALS patients, and were not well tolerated. The initial large trial of subcutaneous BDNF showed that it was well tolerated, but did not show an overall benefit. However, there was an apparent benefit in some groups of patients. Therefore the BDNF trials are continuing. In the study that we are participating in, patients are receiving high doses of BDNF subcutaneously. In another trial at other centers patients are receiving BDNF into the fluid that surrounds the brain and spinal cord (the cerebrospinal fluid) by means of a pump implanted under the skin like a pacemaker. Both these trials are still ongoing.

We have also been part of the international collaborative study of a new drug, named xaliproden, produced by the European pharmaceutical company, Sanofi-Synthelabo. This drug is taken by mouth, is absorbed from the gut and can enter the central nervous system. It acts as a nerve growth factor stimulant. The two studies were both double-blind placebo controlled investigations in which patients received either 1 or 2 mg doses active drug or placebo each day. The trial lasted 18 months, and the patients continue to receive open label active drug treatment. In one study, all patients were co-treated with riluzole. In the other study patient were treated with xaliproden alone. The trials are now completed and analyzed. The drug was well tolerated. There was a general trend for the drug to produce a slowing down of the progression of ALS by 10 to 20%. However, statistical confirmation of this benefit was seen in only of the studies, and the effect was less in patients co-treated with riluzole. The implications of these results are still under discussion.

It is likely that there will be new trials of other neurotrophin stimulant drugs that can be taken by mouth. In the meantime we are involved with a number of other multicenter trials of already available drugs to determine if they will produce a benefit in ALS.

2. Search for New Genes Causing ALS

We are collaborating with Dr. Robert Brown's laboratory in Boston in projects to discover more of the genes responsible for familial ALS, and also to discover the genes that either make sporadic ALS patients susceptible to or protected against developing ALS.

We now believe that the disease process in ALS is like a cascade. (1) There are predisposing factors, particularly gene mutations like those in SOD1 that predispose a person to develop ALS. Dr. Brown is looking for these susceptibility genes, working with us and with other collaborators. (2) There must be precipitating factors in the environment or in the person's body that trigger the initial damage to the motor neurons that marks the beginning of the disease. We suspect what some of these might be, but have no proof about any of them. (3) In many cases there are probably processes in a person's nervous system that protect against or repair this damage. These processes may include the enzyme systems that repair oxidative damage and damage to DNA. These protective processes may prevent the disease of ALS ever appearing, or rarely may lead to remission of the disease. Dr. Brown is looking for these protective genes, working with us and with other collaborators. (4) Finally, there are the processes that lead to the disease spreading and progressing.

When we understand each of these 4 steps in the cascade, we will be much closer to being able to treat and prevent the disease of ALS.

3. Investigation of the Preclinical Stages of ALS

We do not know what is happening to the motor neurons in the years and decades before patients with ALS develop symptoms. An answer to this question would provide us with an insight into the biochemical processes leading to motor neuron degeneration. We are studying the motor neuron function in children of patients with familial ALS to determine the answer to this question. Anyone with a family history of ALS who is interested in taking part in this study should contact us through the website or the email address: wbradley@med.miami.edu.

4. Research Into the Clinical Care of ALS Patients

The Kessenich Family MDA ALS Center is a multidisciplinary clinic devoted to providing all of the broad range of expertise needed for the optimal care of patients with ALS and their families. This is not a new concept, but it is few centers have been able to provide a true multidisciplinary clinic because of the high cost. We are applying research methods to learn more about how best to provide the care of each specialty discipline for patients with ALS and their families. We participate in the ALS Care Program that provides a national registry and data bank on ALS patients. Through this, we are able to undertake research to compare the outcomes of treatment of our patients in the Kessenich Family MDA ALS Center with national figures. We have a home visit program for homebound and ventilator-dependent patients that we are evaluating for the purposes of this research. We participated in the American Academy of Neurology Program to develop the Practice Parameter that describes the best ways to care for patients with ALS. This is now the basis of a national and international education program to raise the standard of care of ALS patients and their families throughout the world.