• FDA Approves Myozyme for Pompe’s Disease
• Arterial Delivery Promising for Muscle Stem Cells
• Three Labs Find Microdystrophin Genes Effective
• New Compound May Save Cells in SMA, ALS
• MMD RESEARCH
• DNA Testing in Type 1
• Brain Chemicals
• Clinical Trials and Studies
  • SMA STUDIES
  • Pre-Trial SMA Study
  • Sodium Phenylbutyrate
  • Valproic Acid, Carnitine
  • Early Mastery of Grammar
  • Closer Look Questions Risks of Medications For People With CMT
  • Statin Treatment May Disclose Metabolic Disorder
  • CellCept Has Risks in Dermatomyositis

FDA Approves Myozyme for Pompe’s Disease by Margaret Wahl 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’s disease, or acid maltase deficiency.   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 development. (Myozyme was approved in the European Union in late March.) The FDA approved the drug for all Pompe’s 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 www.genzyme.com/components/highlights/mz_pi.pdf. 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’s 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’s 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’s 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’s 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.

Arterial Delivery Promising for Muscle Stem Cells

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.”

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 human DMD 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.)

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.

New Compound May Save Cells in SMA, ALS

Representatives of Trophos (www.trophos.com), 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).

MMD RESEARCH

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.

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.

CLINICAL TRIALS AND STUDIES

SMA STUDIES

Several groups are testing compouds in spinal muscular atrophy (SMA), as well as studying neuromuscular and cognitive aspects of this disease.

Pre-Trial SMA Study

Researchers who are part of the Pediatric Neuromuscular Clinical Research Network (www.urmc.edu/sma) are seeking 270 people with types 1, 2 or 3 spinal muscular atrophy (SMA) whose disorder was diagnosed before age 19, to gather data necessary for a future clinical trial. Participating centers are in Boston, New York and Philadelphia, and several visits to these centers are necessary.

Participants will undergo physical exams, lab tests and biopsies. Contact Jessica Rascoll at (212) 342-5767 or jr2024@columbia.edu for more information; or see www.mda.org/research/ctrials.aspx and select SMA from the drop-down menu.

Sodium Phenylbutyrate

A study at the University of Utah in Salt Lake City to test sodium phenylbutyrate remains open for infants who don’t yet have symptoms but have had an SMA diagnosis confirmed by genetic testing.

A recent pilot trial of sodium phenylbutyrate conducted in Europe has suggested that the drug can be safely given and may be beneficial in people with SMA.

For information, contact Sandra Reyna or see www.mda.org/research/ctrials.aspx.

Valproic Acid, Carnitine

A study that combines valproic acid with carnitine for children and adolescents with types 2 or 3 spinal muscular atrophy has opened at five U.S. centers.

Participants will be placed in two groups: Group 1 is for children with SMA who are between 2 and 8 years old and can sit independently but can’t walk. Group 2 is for children with SMA who are between 3 and 17 years old and can stand or walk.

Laboratory experiments have suggested that valproic acid may increase production of full-length SMN, the protein needed but deficient in SMA. Carnitine is a molecule that transports fatty acids (metabolic fuel) into the mitochondria, the cells’ energy production centers.

For information, contact Sandra P. Reyna, Clinical Trials Manager, at (801) 581-3551 or sandra.reyna@ genetics.utah.edu; or see www.mda.org/research/ctrials.aspx.

Early Mastery of Grammar

In a small study, children 1.5 to 3 years old with type 2 SMA came out ahead of their able-bodied peers on an indicator of grammar mastery, say investigators at University College London. Their mastery of vocabulary, however, wasn’t better than that of their able-bodied peers until they reached age 2.

Jechil Sieratzki and Bencie Woll, who published their latest findings in the November issue of the European Journal of Paediatric Neurology, say that on average, the SMA-affected children they studied scored in the 78th percentile (better than or equal to 78 percent of their age peers) on the grammar mastery indicator, with three scoring above the 90th percentile.

Their vocabulary scores were ahead after age 2, the point at which learning new words becomes less dependent on exploring the physical environment, Sieratzki said.

“Children with SMA appear to explore language in place of a world they cannot reach, getting to know grammar while able-bodied toddlers are engaged with the physical environment,” the researchers write.

Closer Look Questions Risks of Medications for People With CMT

Worsening of Charcot-Marie-Tooth (CMT) disease as a result of medication use may not be as worrisome as popular belief has portrayed it, say investigators who recently culled data from medical literature and from 209 people in the CMT North American Database, an MDA-funded registry (see www.med.wayne.edu/neurology/clin_programs/Labs/CMT).

Louis Weimer of Columbia University and David Podwall of Albert Einstein College of Medicine, both in New York, found the only drug with certain and potentially severe adverse consequences even after a single dose was vincristine, an anticancer drug.

Other drugs for which suspicions have been raised and for which prudence is suggested are those used to treat HIV/AIDS; the antibiotics metronidazole and nitrofurantoin; phenytoin, used to treat seizures; statins, used to lower cholesterol; the antidepressant sertraline, although not others in the same SSRI class of drugs; and nitrous oxide anesthesia, commonly used in dentistry.

“As with any treatment,” the investigators write in the March 15 issue of the Journal of the Neurological Sciences, “the risk of neuropathy exacerbation must be weighed against expected treatment benefits and available equivalent, alternative treatments.” They say alternatives to the suspect medications are available in almost all instances; and when they aren’t, the suspect drugs can be used with caution and monitoring.

In general, they note, there’s “considerable disparity between the perceived risk of potentially neurotoxic medications and the number of reports in the literature, other than for vincristine.”

Michael Shy, a neurologist at Wayne State University in Detroit, where he co-directs an MDA clinic and is an MDA research grantee, calls the recent paper “important for CMT patient management, since it provides the first in-depth evaluation of medications that might potentially exacerbate CMT.

“The fact that most medications have not adversely affected any form of CMT is good news for patients and emphasizes the need for data rather than theoretical concerns in management decisions involving patients.

“These results also emphasize the importance of patient registries, such as the CMT North American Database, without which much of this information could not have been obtained.”

Neurologist Michael Shy talks to the mother of a new CMT patient.

Statin Treatment May Disclose Metabolic Disorder

Taking cholesterol-lowering drugs in the statin family (such as atorvastatin, simvastatin and others) can reveal a previously hidden metabolic muscle disorder, say researchers from several collaborating institutions who published results online May 2 in Muscle & Nerve. The findings may also have implications for those who already know they have a metabolic disorder or are carriers for one and need to take statins.

When MDA-supported Georgirene Vladutiu at the State University of New York at Buffalo, and colleagues, performed genetic testing on 110 people taking statins and experiencing muscle pain, weakness or other symptoms, they found considerably more underlying metabolic deficiencies than they found in people taking statins who didn’t have muscle symptoms.

Among people taking statins who experienced muscle symptoms, 10 percent had at least one previously undiscovered mutation for CPT2 deficiency or phosphorylase deficiency, or two mutations for myoadenylate deaminase deficiency. Among those with no muscle symptoms, only 3 percent had these mutations.

The investigators hypothesize that statins may trigger symptoms of underlying, pre-existing conditions in muscles already compromised (even subtly) by a metabolic deficiency.

Vladutiu says she hasn’t fully explored the implications of these findings for people who already know they have a muscle-damaging condition, but she recommends a cautious approach with close monitoring of dosage, symptoms and lab values, such as serum creatine kinase (CK) levels, a rough indicator of muscle damage.

She cautions that the new study only applies to three metabolic muscle diseases, although her group plans to study other disorders soon. “So far we have performed a pilot study with these three disorders and are trying to get at other genetic risk factors for the development of a statin myopathy,” Vladutiu said.

“We certainly would not want to frighten anyone into not taking statins, including people with pre-existing muscle abnormalities, because they are important drugs in the treatment of a number of conditions. But there must be a balance, and doctors need to be vigilant in monitoring risk factors in their patients.”

CellCept Has Risks in Dermatomyositis

According to a small study, adding mycophenolate mofetil (MMF, or CellCept) to prednisone in the treatment of dermatomyositis (DM) can allow patients to significantly reduce their prednisone dosages but exposes them to a risk of serious infections.

Prednisone usually is an effective treatment for DM, but with high doses over long periods of time, weight gain and other side effects can be severe.

Julie Rowin at the University of Illinois at Chicago, and colleagues, who published their findings in the April 25 issue of Neurology, studied 10 people with DM for a year, adding 1 gram of CellCept twice a day to their prednisone regimens.

Of the 10, three developed serious infections, one of them fatal. Of the remaining seven, six reduced their prednisone to 12.5 milligrams per day or less, and one wasn’t able to reduce the prednisone that far.

Five of the six whose prednisone was significantly reduced gained strength, and one person’s strength declined slightly.

The investigators say the three serious infections (two respiratory and one skin) were probably a combination of the suppression of the immune system brought about by the drug treatment and the lung and skin manifestations of DM.

They write that the higher than expected infection rate “warrants significant caution in the use of MMF in DM despite the apparent clinical benefit observed in most patients who were able to tolerate the drug.”