NEW TOOLS TO STOP IMMUNE RESPONSE

The body's immune system, with its army of T cells and B cells, mounts an attack on anything it sees as dangerous, including most proteins that look unfamiliar. Most of the time this response is a vital safety feature that wards off infections by viruses and bacteria, but there are at least three situations in which the immune response is harmful, not helpful. In autoimmune diseases, like myasthenia gravis, polymyositis and dermatomyositis, the body mistakenly turns against its own muscle cells. In organ transplants, the body attacks transplanted tissue it sees as foreign. And, gene therapy experiments in mice lead researchers to believe that the immune system may attack cells carrying new genes, especially if the genes are packaged inside viruses.

For decades, doctors have prescribed drugs to block parts of the immune system, but no drug is perfect, and all have serious side effects if taken for a long time. Drug companies are eager to meet the growing demand for better immunosuppressive drugs, and researchers are busy developing them.

BLOCKING FKBP WITH TACROLIMUS

The new drug tacrolimus (FK506, Prograf), useful with organ transplants, is also beneficial with gene therapy, says MDA grantee George Karpati at Montreal (Canada) Neurological Institute. After Karpati gave tacrolimus to mice with Duchenne muscular dystrophy, along with new genes for dystrophin (the protein missing in Duchenne), significantly more muscle fibers contained dystrophin than when mice got the new genes without the drug. The effect lasted at least two months (the last time the mice were examined), even when the tacrolimus was stopped after one month.

Tacrolimus attaches to the protein FKBP inside T cells, which keeps the cells from starting an immune response. The action is similar to that of an older drug, cyclosporine, which attaches to the protein cyclophilin.

BLOCKING IMPDH WITH MICOPHENOLATE MOFETIL

Another new drug, micophenolate mofetil, blocks the enzyme IMPDH. T cells and B cells need this enzyme to produce an immune response, but many of the body's cells outside the immune system don't need IMPDH and probably wouldn't be harmed if it were blocked. That's good news, because it suggests that side effects would be few. So far, the drug is approved for kidney transplant patients, but other uses are being studied.

EATING TARGET PROTEINS

Can something as simple as feeding people a protein prevent their immune systems from attacking it in the future? That's the question researchers at Boston's Brigham and Women's Hospital are asking, basing their studies on intriguing results in mice. In a clinical trial, 515 patients with multiple sclerosis, an autoimmune neurologic disease, are taking Myloral, an experimental drug that's taken by mouth, or a placebo (sham drug) for comparison. Myloral contains myelin basic protein and proteolipid protein, two known protein targets of the immune system in multiple sclerosis.

The researchers are testing the theory that when a protein passes through the digestive tract, T cells may recognize it as "friendly" and therefore tolerate it. MDA grantee Peter Dau at Evanston Hospital in Illinois cautions that "oral tolerance" may be easier to accomplish before a protein becomes a target (for example, before gene therapy is attempted) than after it becomes one (for example, in an existing autoimmune disease).

ANTI-T-CELL VACCINES

It may be possible to "vaccinate" a patient against his own troublesome T cells, says an American and Israeli research team that included MDA Task Force on Genetics member Lawrence Steinman at Stanford (Calif.) University. The researchers injected into mice a protein that can cause an autoimmune disease that resembles multiple sclerosis.

Of the 14 mice that got the disease-causing protein and the anti- T-cell vaccination, only one developed the disease. In two control groups that didn't get the vaccination, 11 out of 15 and 10 out of 13 mice developed the disease. The vaccine, made of DNA for a crucial part of the T cell, apparently turned off the T cells' autoimmune activity. To the researchers' surprise, it neither killed the cells nor turned them off completely; instead, it caused them to produce substances that actually suppressed the immune response. The investigators say the strategy is promising for the treatment of at least some autoimmune diseases.

ALS DRUGS

Myotrophin Almost Out of the Pipeline

Some people with amyotrophic lateral sclerosis will soon be able to get the experimental drug Myotrophin (human recombinant insulin-like growth factor 1, or IGF-1) through a special program set up by the drug companies Cephalon (West Chester, Pa.) and Chiron (Emeryville, Calif.). The "early access program," OK'd by the Food and Drug Administration in June 1996, allows a limited number of patients to get the drug before it has been through the FDA's full approval process. Myotrophin is a nerve growth factor, which was developed in part with the help of MDA-funded research and tested in MDA clinics. To get on the list for candidacy for the early access program, have your physician call (800) 896-5855. The selection of patients will take place the week of Dec. 9, 1996.

BDNF Trial Nears Completion

A 1,100-patient clinical trial of the nerve growth factor BDNF (brain-derived neurotrophic factor) nears completion this fall, with results expected early in 1997. The drug was developed by Amgen (Thousand Oaks, Calif.) and Regeneron (Tarrytown, N.Y.). Much of the multicenter trial was done at MDA clinics.

NEW GENE TRANSPORTER TESTED IN MICE

Earlier this year, MDA grantees Paula Clemens at the University of Pittsburgh and Jeffrey Chamberlain at the University of Michigan were on separate teams that created a "hollow virus" to deliver the gene for dystrophin, the protein missing in Duchenne dystrophy, to muscle fibers. The hollow, or gutted, viral vector (transporter) has none of its own genes, which gives it room to carry the full-size, very large dystrophin gene.

The gutted viral vector doesn't make any viral proteins, although it does have a viral protein coat that lets it reach and attach to muscle fibers. The researchers had hoped the lack of other viral proteins would make this vector more tolerable to the immune system, which generally attacks foreign proteins.

Now, MDA grantees in two separate research teams have taken the gutted vector experiments a step further by trying the vector in mdx (dystrophin-deficient) mice. The teams included MDA grantees Kevin Campbell at the University of Iowa, C. Thomas Caskey at Merck Research Laboratories (West Point, Pa.) and Clemens at Pittsburgh in one group, and H. Lee Sweeney at the University of Pennsylvania in the other.

The new vector delivered a dystrophin-producing gene to a large number of muscle fibers in the mice, but dystrophin diminished after a few weeks in both groups' experiments. The researchers say an immunologic response to parts of the vector or to the dystrophin protein may be the culprit.

Immunosuppression for gene therapy may be needed. Scientists are trying to determine why some of the dystrophin seems to gradually disappear after gene therapy, and are working on the challenge of delivering the vector in a more efficient way than by intramuscular injections.

BOYS WITH DMD OR BMD NEEDED FOR STUDY

Neuropsychologist Veronica Hinton at Columbia University's Gertrude Sergievsky Center in New York is looking for boys up to age 16 with Duchenne or Becker dystrophy and, where possible, their unaffected siblings, for a study of intellectual strengths and weaknesses in this condition. Some of the study participation can be by mail. If you're interested, call Hinton at (212) 305- 2512, or write to her at 630 W. 168th St., New York, NY 10032.

PROTEIN AT FIBER'S EDGE MAY BE INVOLVED IN LGMD

MDA grantee Kevin Campbell at the University of Iowa led a team that described yet another protein that can, if missing, lead to limb-girdle muscular dystrophy.

Identification of the new protein, delta sarcoglycan, was first reported in August by an Italian group and, more recently, directly connected to the disease by an Italian and Brazilian research team. Members of Campbell's team reported their findings at an October 1996 conference on LGMD in Tunis, Tunisia.

Delta sarcoglycan is part of a cluster of proteins at the border of muscle fibers that probably keeps the muscle fiber from tearing as it contracts. The cluster is made of proteins known as sarcoglycans, dystroglycans, dystrophin and merosin.

Loss of dystrophin results in Duchenne muscular dystrophy; loss of merosin in a form of congenital muscular dystrophy; and loss of alpha, beta or gamma sarcoglycan in LGMD.

Delta sarcoglycan closely resembles gamma sarcoglycan, but its gene is on a different chromosome. The gene for gamma sarcoglycan is on chromosome 13, and the gene for the new protein is on chromosome 5.