Research Updates July-August 2006

Article Highlights:

Research updates as of June 2006

by Margaret Wahl on July 1, 2006 - 2:41pm

QUEST Vol. 13, No. 4

FDA approves Myozyme for Pompe disease

Dr. Chen
During the 1990s, MDA grantee Yuan-Tsong Chen at Duke University in Durham, N.C., engineered an altered form of acid maltase that became the foundation for Myozyme’s developmen

In April, the U.S. Food and Drug Administration approved Myozyme, a laboratory-engineered form of the acid maltase enzyme, as a specific treatment for Pompe disease, or acid maltase deficiency.

(Myozyme was approved in the European Union in late March.)

The FDA approved the drug for all Pompe patients but cautioned that Myozyme has mainly been studied in infants with the disease and that therefore its efficacy and safety can’t be assured for other age groups.

In its April 28 press release, the agency noted that life-threatening immune reactions have occurred with Myozyme, which must be infused intravenously.

According to Genzyme, the Cambridge, Mass., company that developed the drug, only eight out of 280 people (3 percent) who have received Myozyme so far have experienced severe or significant immune responses.

Complete information about the drug, with caveats, is available at

Details of two studies in babies and young children were presented at a meeting of the American College of Medical Genetics in San Diego in March. Details of an observational study of adults with late-onset Pompe were presented last year at a meeting of the World Muscle Society in Brazil.

MDA assisted with the trials.

Of 18 children who began treatment with Myozyme when they were 6 months old or younger, all were alive one year later. Fifteen out of the 18 (83 percent) were free of invasive ventilator support; and 13 (72 percent) acquired new motor milestones, including independent walking in some cases.

Of 21 children who began treatment between 6 months and 3 years of age, 16 (76 percent) remained alive after one year. Those who didn’t need invasive ventilation at the start of the study remained free of it. Ten children (48 percent) reached new motor milestones.

The FDA approved Myozyme for adults and children with Pompe disease, while cautioning that its efficacy and safety have only been clearly established in infants.

When Genzyme studied people with late-onset (after age 1 year) Pompe’s disease, they observed that the average age of symptom onset in their group of 58 adults was 29; that the first symptom in 54 of 58 (93 percent) was weakness in the muscles close to the center of the body; that all patients could walk; and that there was no statis-tically significant disease progression during six months of observation.

Pompe disease patients who have participated in a clinical trial or expanded access program for Myozyme should contact their local study investigators for further instructions.

Genzyme recommends that those whose Pompe disease has just been diagnosed or who haven’t been receiving Myozyme discuss the treatment with their physicians and call Genzyme Treatment Services at (800) 745-4447 to discuss the financial aspects of treatment with this drug.

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Arterial delivery promising for muscle stem cells

Louis Kunkel
Louis Kunkel

When dystrophin-deficient mice with a disease resembling Duchenne muscular dystrophy (DMD) received an injection of muscle-derived stem cells carrying human microdystrophin genes (see “Three Labs”) into a major leg artery, they made more dystrophin than did other mice that received stem cells injected into a vein.

Estanislao Bachrach and colleagues at Children’s Hospital in Boston used cells taken from adult mouse skeletal muscles and then further purified them to obtain a “side population” of cells previously shown to have muscle progenitor (stemlike) capabilities. The team announced its results online April 21 in Muscle & Nerve.

Based on the expression of microdystrophin or green fluorescent protein (GFP) transgenes in host muscle, sections of the recipient muscles exhibited 5 percent to 8 percent of skeletal muscle fibers.

However, when the cells were injected into the large femoral artery, after the vessel was exposed through a surgical incision, three out of four mice started producing dystrophin in 8 percent of their muscle fibers in one examined section, and one mouse produced dystrophin in 7 percent of its fibers in two sections.

“Our successful delivery of adult muscle progenitor cells to the muscle of dystrophin-deficient mice reinforces the utility of intra-arterial delivery of cells as a viable approach for cell-based clinical therapies of primary myopathies [muscle diseases],” the researchers write. “Intra-arterial injection is considered to be a safe, simple, and common clinical procedure.”

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Three labs find microdystrophin genes effective

Good news about miniaturized (mini- and micro-) dystrophin genes has recently come from three labs, all of which have received MDA support. Dystrophin genes are the instructions for the muscle protein dystrophin, missing in boys with Duchenne muscular dystrophy (DMD).

Dongsheng Duan and colleagues at the University of Missouri-Columbia and Jeffrey Chamberlain and colleagues at the University of Washington-Seattle have shown that microdystrophin genes missing instructions for a section at one end, called the C terminal (blue), and part of a midsection called the central rod domain (green), can provide effective treatment for mice with a severe disease resembling DMD.

Duan’s group, which published results online March 21 in Molecular Therapy, inserted microdystrophin genes originally developed in Chamberlain’s lab into transport vehicles made from adeno-associated viruses. They then injected them into the leg muscles of mice missing both dystrophin and utrophin.

These mice, known as double knockouts, develop a disease that more closely resembles humanDMD than do mice missing dystrophin alone.

They found the new genes eliminated scarring and inflammation in the treated muscles, increased muscle force, reduced contraction-related damage, and restored muscle cell membrane proteins to their appropriate positions.

The highly truncated genes also allowed syntrophins and dystrobrevin — proteins thought to carry signals in muscle — to take their places near the cell membrane.

Chamberlain’s group went a step further by delivering the gene systemically to double knockout mice. They also used adeno-associated viral transport vehicles, but they delivered the genes intravenously.

Reporting their results at the New Directions in Skeletal Muscle Biology conference held in Dallas in April, the team said they saw dystrophin production in limb and respiratory muscles, increased muscle function, and a longer life span in the treated, compared to the untreated, mice.

Also this spring, researchers associated with the laboratory of Robert White at the University of Missouri-Kansas City, including MDA grantee Stephen Hauschka at the University of Washington, used an entirely different type of microdystrophin gene and found that it, too, conferred significant benefits.

This group bred double knockout mice to produce in their skeletal muscles a form of dystrophin normally found only in the eye’s retina. This form of dystrophin, known as Dp260, is missing the N terminal (pink), at the opposite end of dystrophin from the C terminal, as well as some of the midsection of the protein. The N terminal is involved in anchoring dystrophin to the inside of the cell.

This team announced in the March issue of Neuromuscular Disorders that the mice bred to produce Dp260 developed only a very mild muscle disease, grew and gained weight normally, and had spinal curvatures like those seen in normal mice, in contrast to the severe curvatures that double knockout mice develop. They also lived longer than their untreated counterparts. (An earlier report from Chamberlain’s lab showed that Dp260 could partially protect dystrophin-deficient muscles in mice.)

New compound

To restore muscle cell function, two factors appear to be necessary: dystrophin’s dystroglycan binding domain (orange), where it attaches to the dystroglycan protein in the muscle cell membrane, and at least some of the central rod domain.

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New compound may save cells in SMA, ALS

Representatives of Trophos, a biopharmaceutical company in Marseille, France, announced at an April meeting of the American Academy of Neurology that the company plans to test an experimental compound called TRO19622 in people with spinal muscular atrophy (SMA) before the end of the year.

TRO19622 appears to work by stopping a cell death program that may play a role in SMA. An early step in the program is the opening of pores in the energy-producing units inside cells known as mitochondria. When these pores open, fluid rushes in, and a membrane surrounding the mitochondrion can rupture, allowing a chemical trigger for cell death to leak out.

The compound, which was discovered by Trophos as part of a screening program to find chemicals that keep nerve cells alive, has a cholesterol-like structure and apparently interferes with the opening of mitochondrial pores. The company also plans to test the drug in amyotrophic lateral sclerosis (ALS).

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Scientists now know there are two major forms of myotonic muscular dystrophy (MMD) — type 1 (MMD1), which arises from an expanded stretch of repeated DNA sequences (repeats) on chromosome 19; and type 2 (MMD2), which arises from a similar expansion on chromosome 3. In type 1, a small DNA expansion tends to get larger, and the disease more severe, with each generation.

Researchers are continuing to work out the details of these disease mechanisms, with an eye to both treatment and prevention of MMD.

DNA testing in type 1

Researchers at several institutions in Quebec Province in Canada studied 102 people with MMD symptoms in themselves or family members and have confirmed that people with slightly expanded DNA repeat sections on chromosome 19 are unlikely to have MMD1 symptoms by middle age. That, they say, makes genetic testing for this population imperative in determining risks to future children.

MMD Patients
Canadian researchers recommend that young adults at risk for MMD1 undergo genetic testing.

A normal maximum number of repeats is 37, and the MMD disease range is generally considered to be between 50 and 4,000.

Marie-Eve Arsenault at Carrefour de Sante in Jonquiere, Quebec, and colleagues, report in the April 25 issue of Neurology, that most people with 50 to 99 CTG repeats in their study had no symptoms other than cataracts in their eyes.

They found, however, that those with 100 to 200 repeats — a size to which the smaller segments are likely to expand as the DNA is passed to the next generation — were much more likely to have MMD symptoms. These included myotonia (delayed muscle relaxation), weakness, excessive daytime sleepiness, and abnormal electromyogram tests, in addition to cataracts.

They recommend genetic testing of at-risk family members. “This is particularly important for young adults of reproductive age,” to allow early detection and genetic counseling, the investigators write.

Brain chemicals

When researchers at Otto von Guericke University in Magdeburg, Germany, performed magnetic resonance spectroscopy (MRS) imaging studies on the brains of 14 people with MMD1 and 15 people with MMD2, they found similar structural abnormalities but dissimilar levels of some metabolic compounds.

Only MMD1 patients showed depletion of brain creatine and choline, while both groups showed significantly reduced levels of brain N-acetylaspartate compared to those of unaffected study participants.

The researchers, who published their findings online April 26 in Muscle & Nerve, conclude that the two forms of MMD differ in their nerve cell abnormalities.

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