May 1, 2007

MINOCYCLINE INEFFECTIVE FOR ALS;
NEWS FROM AAN ANNUAL MEETING

Disappointing results of a nine-month trial of the drug minocycline for amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) were announced today at the American Academy of Neurology Annual Meeting in Boston.

Minocycline demonstrated no beneficial effect, and for some patients, worsened measurable outcomes.

People with ALS who are currently taking the drug, an antibiotic in the tetracycline family, are urged to contact their physician to discuss discontinuing its use, said MDA Medical Director Valerie Cwik, who is at the meeting.

The drug did not affect survival or quality of life measures for people with ALS in the trial.

The trial tested minocycline versus a placebo (inert, look-alike substance) in 412 people at 31 U.S. centers. The drug was thought to reduce inflammation and counteract cell death.

ADDITIONAL HIGHLIGHTS FROM THE AAN ANNUAL MEETING (April 28-May 5, Boston)

DUCHENNE AND BECKER MD

  • An analysis of a large database of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) reveals that severity of the disease cannot always be predicted from analysis of the genetic mutation. About 10 percent of the time, mutations that predict the more severe DMD actually turn out to be the less severe BMD.

  • Delivering therapeutic genes for the muscle protein dystrophin to a whole limb at a time, via the bloodstream, to treat Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), is feasible, suggest tests in a dystrophin-deficient mouse and a larger animal. The best delivery systems were viral shells called AAV6 and AAV8.

  • A drug called idebenone, which may increase cellular energy production, improved heart function and exercise performance in dystrophin-deficient mice with a disease resembling Duchenne muscular dystrophy (DMD).

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

  • A 20-week trial of sodium phenylbutyrate in 40 people with amyotrophic lateral sclerosis (ALS) at eight centers showed the drug was safe and tolerable for the majority of participants at dosages between 12 and 21 grams per day.

  • An analysis of muscle tissue in 33 people with amyotrophic lateral sclerosis (ALS), ALS with dementia or dementia alone, seven people with various other neuromuscular disorders, and 12 people without a neuromuscular disorder showed that a protein in muscle called Nogo-A was found in 20 out of 23 (87 percent) of the ALS patients. It was also found in five out of five people with ALS and dementia (100 percent) and three out of five with dementia alone (60 percent). None of the other 19 study participants, who had another neuromuscular disease or no neuromuscular disease, had this protein in their muscle tissue. The significance of these results isn’t yet clear.

  • Rats with amyotrophic lateral sclerosis (ALS) caused by mutated SOD1 genes were helped by a compound called antisense that was designed to keep cells from following the erroneous genetic instructions that would produce an abnormal and toxic SOD1 protein. Onset of symptoms wasn’t affected, but early disease progression was slowed, and survival was extended by a month. The study supports the use of this type of therapy for SOD1-related ALS.

  • Cells called microglia taken from the nervous systems of mice with amyotrophic lateral sclerosis (ALS) caused by mutated SOD1 genes are more toxic when active than are microglia taken from healthy mice. Microglia are the cells that carry out an immune response in the nervous system. The study supports the hypothesis that activated microglia play a role in ALS.


MYOTONIC DYSTROPHY

  • Using antisense technology to change the way muscle cells interpret genetic information for the so-called chloride channel protein was effective in a mouse model of type 1 myotonic dystrophy (MMD). The treatment restored normal chloride channel production and relieved myotonia (prolonged muscle contractions) in the mice.

LIMB-GIRDLE MD

  • Doctors were able to identify the precise molecular defect in 148 of 328 people (44percent) with severe limb-girdle muscular dystrophy (LGMD) and in 40 of 292 (14 percent) with less severe LGMD. However, in many with LGMD, a precise diagnosis remains elusive. To date, 19 different genetic mutations have been found to cause LGMD.

  • The microscopic appearance of muscle fibers in mice with dysferlin-deficient limb-girdle muscular dystrophy (LGMD2B) was improved by blocking a group of immune-system proteins called complement.


OCULOPHARYNGEAL MD

  • An 18-year study of six people with a genetic mutation in each of their two PABPN1 genes found that such patients develop very severe oculopharyngeal muscular dystrophy (OPMD), which normally results from only one PABPN1 mutation. All six developed drooping eyelids and difficulty swallowing before age 30. They later developed weak eye movement muscles, trouble speaking, limb weakness and cognitive deficits. Five required feeding tubes.


FACIOSCAPULOHUMERAL MD

  • An analysis of 50 children with the rare early childhood form of facioscapulohumeral muscular dystrophy (FSHD) confirmed earlier reports that this form of FSHD is more severe than adult FSHD. The majority had facial and other muscle weakness and muscle pain. Other problems reported more frequently in the infantile form of FSH were hearing loss, respiratory effects and requiring a wheelchair by age 18.

POMPE’S DISEASE

  • Analysis of 58 people with late-onset Pompe’s disease (also known as acid maltase deficiency or AMD) revealed slow progression of limb and respiratory muscle weakness over a year’s time is probably typical. The average respiratory muscle test score dropped by 3.5 percent and the average leg muscle test score by 3.2 percent. The average age of symptom onset was 29.


MYASTHENIA GRAVIS

  • A congenital myasthenic syndrome (disturbance of nerve-to-muscle signal transmission due to a genetic mutation) that results from a mutation in the gene for dok-7, a protein found at the junction of nerve and muscle, was described in 13 patients. The investigators said this type of myasthenia probably involves ongoing destruction and remodeling at the neuromuscular junction.

  • Adding the immune-system suppressant mycophenolate mofetil (CellCept) to prednisone, a standard immune-system dampener, in patients with myasthenia gravis (MG), failed to improve strength, ability to perform daily activities or biochemical measurements of disease activity. MG is a disorder in which the immune system mistakenly attacks parts of the nerve-muscle junction. Participants took either prednisone at 20 milligrams per day plus 2.5 grams per day of CellCept, or prednisone plus a placebo (look-alike inactive substance) for three months.

  • When the investigators examined the records of 21 patients who were treated for 24 episodes of myasthenic crisis (myasthenia-related respiratory failure) between 1987 and 2006, they found that 14 (58 percent) of the episodes were successfully treated with noninvasive methods alone. Noninvasive ventilation support is pressurized air supplied through a mask or oral or nasal interface; invasive ventilation support is pressurized air delivered through a surgically created hole in the trachea (tracheostomy).


LAMBERT-EATON SYNDROME

  • Lambert-Eaton syndrome (LES), a type of myasthenia in which the immune system attacks the part of the nerve fiber from which signals are transmitted to muscle, is sometimes found in conjunction with small-cell lung cancer; and when it is, it appears to improve the cancer survival rate. At five years after diagnosis, 36 percent of patients with this type of cancer and LES were alive, which was significantly greater than the survival rate in the general small-cell lung cancer population. (LES may reflect the immune system’s efforts to attack the cancer, with off-target effects on the nerve-muscle junction.)

STEM CELL RESEARCH

  • Mouse embryonic stem cells injected into the skin or muscle tissue of other mice only survive if the recipients have the same genes as they do or have suppressed immune systems. They also form tumors and don’t necessarily become muscle after being injected into muscles. The studies suggest molecular modifications will have to be made to embryonic stem cells before they can be used in human muscles.