Several recent studies by MDA-supported researchers have furthered interest in the possible benefits of targeting muscle instead of nerve tissue as a means to slow loss of strength in people with ALS, traditionally considered a nervous system disease.
One potential muscle-targeting therapeutic strategy involves manipulating or blocking a protein in the body called myostatin, which normally limits muscle growth. The strategy also is being investigated in muscle diseases.
Although “myostatin blockade” doesn’t appear to influence survival in mice with a disease resembling ALS, it has been shown to improve muscle size and strength, even as motor neurons, which send signals to muscle and fail in ALS, continue to be lost.
Such effects could contribute to improved quality of life for people with ALS.
|In ALS, the motor neurons, which normally send signals to muscle fibers via a neuro-transmitter called acetylcholine, degenerate. As motor neurons fail, their fibers retract, and signaling to muscle fibers is disrupted. Most ALS therapies in development target the motor neurons or other cells in the nervous system. Myostatin blocking targets the muscle fibers, with the goal of maintaining strength and function even as nerve cells fail.
Member of a family of growth-regulating hormones
Myostatin belongs to the transforming growth factor-beta (TGF-beta) family of proteins involved in the normal development of muscles. Its role is to inhibit muscle-fiber growth and regeneration, and scientists are working to understand precisely how it does its job so that they can devise ways to interfere with or stop it.
Structural biologist and MDA grantee Tom Thompson at the University of Cincinnati, and colleagues, recently characterized the structure of the myostatin protein at the atomic level, something Thompson hopes will allow the academic community and the pharmaceutical industry “to make use of the information in their efforts to design myostatin inhibitors.”
The investigators published their results in the Sept. 2, 2009, issue of the European Molecular Biology Organization (EMBO) Journal.
Prior to the study, the specific structure of myostatin was unknown, Thompson says. “We understood that it was part of this family of proteins that looked similar, but we didn’t have the details. From this work we were able, for the first time, to pick out key details of what myostatin looks like.”
Thompson explains that knowing the protein’s structure offers clues as to how it works and functions in the body, and says he believes it “will make the jobs of companies putting effort into myostatin therapy a lot easier.”
Blocking a blocker
“There is an extensive effort being directed at developing drugs capable of blocking myostatin signaling,” says Se-Jin Lee, a geneticist and MDA grantee at Johns Hopkins University School of Medicine in Baltimore.
In 1997, Lee created a strain of mice lacking the gene for the myostatin protein and showed that they developed more muscle and greater strength than mice with normal myostatin genes. “Most of this effort has focused on biologics capable of binding [sticking to] myostatin and inhibiting its activity,” he says.
One method to block myostatin involves using neutralizing antibodies (immune system proteins) that stick to myostatin and interfere with its signaling actions.
Wyeth Pharmaceuticals of Madison, N.J., developed such a compound, called MYO-029, and, with supplemental funding to trial sites from MDA, tested it beginning in 2005 in adults with muscular dystrophy.
Although investigators found the compound was safe and well tolerated, the study was not designed to assess muscle strength and function, and the company announced in March 2008 that it would not continue development of MYO-029 for muscular dystrophy.
In a second approach to myostatin blockade, a mutated propeptide (or “precursor,” an immature form of the myostatin protein) inhibits myostatin by binding to it and forming an inactive complex that is unable to stick to its receptor. (A receptor is a protein molecule that prompts signaling when docked with its partner.)
Amgen, a biotechnology company headquartered in Thousand Oaks, Calif., has completed healthy volunteer studies for its myostatin inhibitor, AMG745, under development to treat muscle disorders.
A third strategy achieves blockade through inhibition of the normal binding of myostatin with its usual receptor, activin receptor type 2B. A nonfunctional, partial molecule that contains a portion of the usual receptor is introduced. This “decoy” receptor sticks to myostatin, effectively keeping it away from its regular, functional receptors.
“The myostatin will bind to these decoy receptors similarly to how it would bind to its natural receptor,” but without all the components of its natural binding partner it’s unable to send signals, says MDA grantee Kathryn Wagner, who is director of the Center for Genetic Muscle Diseases at the Kennedy Krieger Institute in Baltimore and co-director of the MDA Clinic at Johns Hopkins University in that city. “Essentially, it sops up the myostatin and stops it from signaling.”
On Sept. 10, 2009, biopharmaceutical company Acceleron Pharma of Cambridge, Mass., released phase 1 clinical trial results on its soluble receptor ACE031, developed to treat loss of muscle mass and function.
“Acceleron’s data showed increased lean body mass and increased muscle size in healthy volunteers receiving a single dose of the soluble receptor,” says Lee. “These results are very exciting, as this is the first clear indication that this general strategy may work in humans.”
More, stronger muscles in ALS mouse model
Wagner and MDA grantee Brett Morrison of Johns Hopkins, and colleagues, published study results on a “mouse version” of Acceleron’s ACE031 in the June 2009 issue of Experimental Neurology.
The investigators described studies in which mice with an ALS-like disease were treated with a soluble activin receptor type 2B. These mice experienced delay in the onset of weakness, increased body weight and improved grip strength in tests where treatment began before symptom onset and also in tests where treatment was initiated after symptoms began.
Treatment with the decoy receptor did not increase length of survival
“The remaining muscle fibers are probably stronger, and therefore allow the animal to compensate while the loss of motor neurons continues,” Wagner explains, noting that evidence for this is the lack of increased survival time in the treated mice. “So because the remaining motor units [the motor neurons and the muscle fibers to which they send signals] are larger and stronger, there’s a longer time before significant weakness occurs in the mouse. We hope that would translate to a longer time before significant disability in humans.”
If the remaining muscle is stronger, then people with ALS and other progressive muscle diseases might be able to manage the activities of daily living longer, increasing their quality of life, Wagner adds, “by making them stronger while they have the disease.”
Although the study looked at SOD1 mice, engineered to model a familial form of the disease caused by a mutation in the superoxide dismutase 1 gene, this type of treatment wouldn’t be specific to the SOD1 form of ALS.
“Quite the opposite,” Wagner says. “It’s a common strategy that we’re looking at now in both muscular dystrophy and ALS. We’re not influencing the underlying pathophysiology, we’re just making more, stronger muscles.”
Working toward cures and treatments simultaneously
“Many researchers in ALS are working toward a cure,” Morrison acknowledges. “But it is our hope that treatments that improve atrophy and weakness could be available right now to provide functional benefits in patients and improve quality of life for years.”
He notes that such treatments may allow people with ALS to avoid a wheelchair, continue to feed themselves or maintain enough strength to speak without assistance, for additional months or, possibly, years.
MDA researchers continue to home in on refining the ways in which myostatin and the TGF-beta signaling pathway might be targeted to help those with muscle atrophy and weakness, as well as how such strategies may be combined with the addition of neurotrophic (muscle-nourishing) factors, such as insulin-like growth factor 1 (IGF1), and exercise.
“I feel with both muscular dystrophy and ALS that we need to have treatments right now in addition to pursuing cures,” Wagner says. “If we let generations go by focusing only on cures, then we’re not doing enough for the current patients.”