NEW INSIGHTS, DRUGS IN ALS

The results of a 152-patient, seven-center trial of gabapentin (brand name Neurontin) for amyotrophic lateral sclerosis were recently released.

The data suggest that gabapentin, which probably decreases production of the central nervous system chemical glutamate, shows promise in slowing loss of strength in people with ALS. Further studies are needed to confirm these results.

The drug riluzole (Rilutek), approved for use in ALS by the Food and Drug Administration in December, also reduces glutamate, but probably in a different way.

Gabapentin is now marketed for epilepsy (seizures) by Parke-Davis. If further studies are positive, the FDA may approve gabapentin for the treatment of ALS.

Robert Miller, MDA clinic director and Forbes Norris MDA/ALS Center director at California Pacific Medical Center in San Francisco, was the lead investigator on this study. Six of the seven study centers were MDA clinics.

FRIEDREICH'S ATAXIA GENE FOUND

MDA grantees Massimo Pandolfo and Sanjay Bidichandani at Houston's Baylor College of Medicine led a team that identified two types of mutations in a chromosome 9 gene that can lead to Friedreich's ataxia.

The disease, which usually begins in adolescence, causes progressive loss of coordination and leg weakness, with difficulty walking and speaking. Heart problems are common, and diabetes occurs about 10 percent of the time.

Friedreich's ataxia is a recessive disease, meaning flawed genes from both parents are needed to produce symptoms.

The gene Pandolfo's team found codes for a small protein he's called "frataxin," found in tissues affected by the disease. Researchers don't yet know what it does, but they suspect that in Friedreich's ataxia there isn't enough of it.

In almost all the patients studied, the genetic mutation is of the type known as an "expanded triplet repeat," a string of three nucleotides (DNA units) repeated too many times. A few patients had a different kind of gene flaw in one of their frataxin genes. Called a "point mutation," this type of flaw involves the substitution of one nucleotide for another in the DNA code.

If the problem in Friedreich's ataxia is a lack of frataxin, therapies might be developed to make up for it.

MDA, AFM MEET ON GENE THERAPY

MDA and the French AFM (Association Francaise Contre les Myopathies, or French "MDA") recently sponsored a meeting of some 50 doctors and scientists in Lisses, France, to discuss strategies for gene therapy in Duchenne and Becker muscular dystrophies. The meeting was a follow-up to an MDA/AFM gene therapy meeting held in Tucson, Ariz., in November 1994. It focused on which protein, which vector (gene delivery vehicle) and which overall delivery strategy to use.

In Duchenne and Becker dystrophies, a variety of mutations in the X chromosome gene for dystrophin cause either a complete lack of dystrophin and the severe Duchenne dystrophy, or a partial lack of dystrophin and the less severe Becker dystrophy.

Most gene therapy strategies aim to put new dystrophin genes into muscle fibers, using a virus to deliver them. Serious obstacles, however, remain. First, the dystrophin gene is too big to fit inside a virus. Miniaturizing the gene has been a focus for several MDA grantees, among them Jeffrey Chamberlain at the University of Michigan and Paula Clemens at the University of Pittsburgh. Experiments have shown that some "minigenes" work better than others.

Not all researchers think inserting dystrophin is the right strategy. British researcher and MDA grantee Kay Davies has been studying the use of utrophin, which is similar to dystrophin but made from a chromosome 6 gene. Animal experiments are under way to see whether utrophin could substitute for dystrophin.

Most conference participants are using viruses to insert new genes, but a few are trying non-viral vectors. The question of which virus to use and how to modify the viruses was discussed at length.

The adenovirus is still the most popular vector. Clemens reported on her success in "gutting" an adenovirus -- removing almost all its own genes, making room for a fairly large dystrophin gene and probably reducing the chances of the virus being rejected by the immune system.

Hansell Stedman, a surgeon at the University of Pennsylvania who lost a brother to Duchenne dystrophy, described a technique for shutting off blood flow to some organs (such as the liver) and increasing it to muscles for the targeted delivery of dystrophin genes.

STUDIES PROBE HOW STEROIDS WORK

Steroid drugs like prednisone and prednisolone have been used for decades for many autoimmune disorders. In these conditions, which include the neuromuscular diseases myasthenia gravis, polymyositis and dermatomyositis, the body's immune system mistakenly attacks its own tissues. But, until now, little has been known about how these drugs work, making it hard for drug companies to develop agents that might be just as effective but have fewer side effects.

Recent studies show steroids probably block a cellular chemical called nuclear factor kappa B, a key trigger of an immune response. According to Jeffrey Leiden at the University of Chicago, the kappa B finding, if confirmed, will solve a problem that has puzzled people for a long time and could lead to better drugs for autoimmune conditions.

SMA MOUSE

MDA grantee Lucien Houenou at Wake Forest University in Winston-Salem, N.C., is studying mice with spinal muscular atrophy (SMA).

The animal, first developed in France and known as the paralyse mouse, has a motor neuron disorder that Houenou says looks more like SMA than any other "mouse model" of the disease so far studied.

Mouse models are crucial tools for testing new treatments, and Houenou's group is planning to test neurotrophic factors on this mouse.