Inhibition of myostatin via follistatin as a therapy for muscle disease.

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Potential clinical applications for muscular diseases in general .

A number of studies have considered the possible benefits from inhibiting myostatin and thereby increasing muscle mass for treating patients with various types of muscular dystrophy, see Haidet, et al (2008) and Rodino-Klapac, et al (2009) for reviews.


Table from Rodino-Klapac, et al (2009).


The clinical application of Myostatin based therapy in sIBM


The Myositis Association (TMA) are pleased to inform you that the Follistatin gene transfer for inclusion-body myositis has cleared its last regulatory hurdle and recruitment of patients begins this December [2011] . The trial to be conducted at Nationwide Children's Hospital in Columbus, OH expects to select patients in December to be enrolled, with the first patient injection to begin in January, 2012. The group at Nationwide Children's have worked hard to begin what we hope will be helpful to patients with sIBM to improve muscle strength. TMA will keep in touch with the investigators regarding the progress of the trial.


SciBX Distillery: Therapeutics - Musculoskeletal disease

[SciBX: Science-Business eXchange is a weekly publication that unites the scientific acumen of Nature Publishing Group with the business intelligence of BioCentury Publications, Inc.]

SciBX 2(47); doi:10.1038/scibx.2009.1733 Published online Dec. 10 2009

Myostatin (GDF-8)
INDICATION: Musculoskeletal disease
Summary Studies in macaques suggest that follistatin gene therapy could help treat muscle diseases. Follistatin is a naturally occurring inhibitor of myostatin, a protein that prevents growth of muscle tissue. In cynomolgus macaques, quadriceps injection of an adeno-associated virus expressing follistatin led to greater muscle strength and size than no treatment. Also in the monkeys, long-term intramuscular delivery did not result in toxicity or organ damage. Toxicology and biodistribution studies are ongoing, and the researchers plan to start Phase I testing in 2010 to treat muscle diseases characterized by weakening of the quadriceps muscle.
Acceleron Pharma Inc.'s ACE-031, a myostatin inhibitor, is in Phase I testing to treat muscular dystrophy. Amgen Inc.'s myostatin inhibitor, AMG-745, is in Phase I testing to treat muscular atrophy.
Licensing Status Multiple patent claims filed by The Research Institute at Nationwide Children's Hospital covering use of follistatin gene therapy to improve muscle mass and muscle function to treat musculoskeletal and neuromuscular disorders; Institute is seeking to partner and/or license the technology
Reference 1. Kota, J. et al. Sci. Transl. Med.; published online Nov. 11, 2009; doi:10.1126/scitranslmed.3000112 | Article Contact: Brian K. Kaspar, The Ohio State University, Columbus, Ohio e-mail: KasparB@pediatrics.ohio-state.edu Contact: Jerry R. Mendell, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio e-mail: jerry.me

This related article provides an objective overview: Following up on follistatin


Panel reviews past, current and future myositis research

Ever wonder why there's always a limit to how big muscles can get? It's because of myostatin, a protein found in high concentrations in muscles, where it limits muscle growth. Scientists have been fascinated by this protein, reasoning that if it could be controlled, then muscles weakened by disease could experience growth and possibly gain strength.

In 1997, scientists at Johns Hopkins showed that myostatin production is controlled by a gene and 'knocking out' this gene limits myostatin and doubles muscle production in normal mice.

Cattle breeders found a real-life example of what happens when they discovered a mutation that suppressed myostatin in certain kinds of cattle. They've selectively bred cattle with this gene for herds with an abnormally large muscle mass.

This is the path, says Brian Kaspar PhD, showing promise for restoration of quadriceps strength to patients with IBM. The myostatin-muscle connection has prompted the study by the team he leads, with Dr. Jerry Mendell, at The Research Institute at Nationwide Children's Hospital.

There are several ways to suppress myostatin, but careful studies with mice show that follistatin, also a protein, seems to be the most effective. Scientists have identified the gene controlling follistatin production, allowing research on the potential control of myostatin production to move forward. A 2008 trial showed that the systematic suppression of myostatin did not appear to pose any danger to a group of muscle disease patients.

Although other muscles are affected by inclusion-body myositis, the quadriceps is the most important, Dr. Kaspar said. Weakening of this main leg muscle causes falls and greatly affects independence, so researchers are focusing on the potential increase of strength in quadriceps muscles of mice and monkeys, although increased size in other muscles has also occurred and is expected.

Significant increases in strength and individual muscle weight were seen in mice that the Mendell-Kaspar team treated with follistatin. This was true even when the mice were old, Kaspar said, an important consideration since IBM occurs in aging bodies. Researchers also needed to prove that suppression of myostatin did not affect reproduction in the treated mice, and that the increased muscle mass translated into realistic everyday function.

Once the Mendell-Kaspar team made these important findings, it was time to move to working with nonhuman primates, monkeys. It was clear from casual observation and also meticulous measuring that monkeys treated with follistatin had significant gains in quadriceps size over the nontreated monkeys, and that their gain in strength was functional. No changes were found that could potentially affect reproduction.

Of special concern was the heart, since it is also a muscle. Careful study showed there were no cardiac implications in the monkeys, nor did autopsies reveal any changes in other organs.

The results have been so impressive that regulatory authorities have speeded up the approval process as the team moves forward. Toxicology studies are just beginning; they'll be finished in about a year (June 2010), Dr. Kaspar said. Human trials will begin shortly afterwards, if all looks good.

The initial study will be of patients with proven IBM who have weakness of knee extensor muscles. Nine patients (three cohorts with three patients per cohort) will receive 3 doses of follistatin, and return for evaluation on days 7, 14, 20, 60, 90, 120, and 180. They'll be assessed as follows:

= Quantitative strength measures of quadriceps muscles and functional tests (stair climbing, walking 30 feet, getting up from chair);

= MRI of quadriceps muscles after 180 days of treatment will be compared with pre-treatment;

= Patients will receive a muscle biopsy on both quadriceps on day 180.

TMA will notify all its members when recruitment for this trial begins.

From The Outlook, Fall, 2009, The Myositis Association.


An interview concerning Gene Therapy for Inclusion-Body Myositis

On November 23/09, Drs. Mendell and Kaspar answered many questions in an hour-long session.
Edited -- Live Discussion with Drs. Jerry Mendell and Brian Kaspar
Gene Therapy for Inclusion-Body Myositis
TMA member: How long until FDA approves a clinical trial for humans and how long would a clinical trial run before deemed safe for humans?
Drs. Mendell and Kaspar:The FDA will answer both questions. We will submit materials in about July 2010 and if things are ok, we will proceed with clinical trial in August 2010.
TMA member: Would the initial clinical trial patients likely be local to Ohio?
Drs. Mendell and Kaspar:The first trial would be here in Columbus, OH, at Nationwide Children's Hospital, and will involve 6-9 patients. If successful, we would expect to move to multiple sites.
TMA member: Do you see this as an ongoing treatment or one time injections?
Drs. Mendell and Kaspar:It is a one-time gene injection, with several injections into the muscles. Our results have shown long-term gene expression in both rodents and non-human primates.
TMA member: Was it HGH that was used to suppress the gene in the monkey trial?
Drs. Mendell and Kaspar:No, we used Follistatin to suppress the myostatin gene in our studies.
TMA member: How long did it take before muscle growth was realized?
Drs. Mendell and Kaspar:About 8 weeks following the injection, one could noticeably see that the muscles were getting bigger.
TMA member: What would be the length of your 1st trial?
Drs. Mendell and Kaspar:The FDA really determines this, likely if successful and safe to extend into Phase II in one year after treatment begins.
TMA member: We've all heard the MDA "doesn't play well with others." Wouldn't they want to kick in funds needed to promote your research specific to this trial?
Drs. Mendell and Kaspar:The MDA has been very supportive of our works on muscle disease. The TMA has generously supported our IBM studies. We are currently requesting support from the MDA who have been very supportive to our research programs in both the Kaspar and Mendell Lab. They have also expressed interest in potentially funding some of the trial, which will be very important for us moving this forward.
TMA member: What side effects do you think will occur during treatment
Drs. Mendell and Kaspar:We currently have not seen any side effects in our mouse or non-human primate studies. We are currently performing the formal safety studies required by the FDA prior to entering human clinical trials.
TMA member: Assuming that the gene therapy works in humans and there is muscle development, what chance do you give to IBM patients to be able to climb steps again or get up from low seats? I assume that physical therapy must also be done.
Drs. Mendell and Kaspar:Yes, we likely would encourage physical therapy in addition to the gene therapy. We are hopeful to slow muscle disease in IBM, and also enhance muscle mass and strength. The trial will shed insight into the success of this.
TMA member: Is the immune system responding to the therapy or simply the muscles?
Drs. Mendell and Kaspar:Muscle is the primary responder. In our rodent studies, we showed that follistatin actually was anti-inflammatory, which would likely be good for IBM.
TMA member: If this therapy does become available, to what extent can the IBM patient experience recovery?
Drs. Mendell and Kaspar:We are hopeful we will be able to preserve and enhance strength in the thigh muscle for patients. Our clinical trials will help to determine the success of this approach. Current studies in mice and non-human primates were very encouraging.
TMA member: How do you go about choosing subjects for a study on people? Can you predict the side effects?
Drs. Mendell and Kaspar:Clinical diagnosis of sIBM. You must submit your name, address, materials surrounding your diagnosis. We will also need to see you in our clinic. Our safety studies, mandated and sanctioned by the FDA, look for any possible safety or side effects to the drug. At this stage we have not seen any adverse reaction or problems.
TMA member: How exactly does gene therapy work? Do you take a pill?
Drs. Mendell and Kaspar:Gene therapy uses viruses, that we make safe. One can imagine the virus as a very tiny bullet, that delivers the gene into the cell. The cell then produces the product, in our case follistatin, that helps to enhance muscle mass and strength. It's a simple injection: no pills are taken for our therapy.
TMA member: Will you be using placebo in your clinical trial?
Drs. Mendell and Kaspar:At this stage, Phase I, all patients would receive the treatment.
TMA member: Do you think flu injections could have some link to causing IBM? I had an injection about 2 years ago and I had a weak arm develop.
Drs. Mendell and Kaspar:There is no data to suggest a link with the flu vaccine and IBM.
TMA member: What was the age of the oldest monkey you achieved success with?
Drs. Mendell and Kaspar:Our monkeys were not infants. They were young to mid adults. We do not see an age effect, that is, in rodents (mice) we see beneficial effects in young and aged mice.
TMA member: Has this specific gene therapy been used on any humans anywhere?
Drs. Mendell and Kaspar:Follistatin, to our knowledge, has not been tested in any human, so this would be the first trial testing follistatin. Our gene delivery agent, Adeno associated virus 1, has been in many patients, with a relatively safe profile in patients.
TMA member: When [what year] was it known this specific gene suppresses muscle growth?
Drs. Mendell and Kaspar:Our work progresses from a seminal discovery on myostatin.
Below is excellent background taken from Wikipedia which is very accurate:
'The gene encoding myostatin was discovered in 1997 by geneticists Alexandra McPherron and Se-Jin Lee who also produced a strain of mutant mice that lack the gene. These myostatin "knockout" mice have approximately twice as much muscle as normal mice. These mice were subsequently named "mighty mice". Naturally occurring myostatin "nulls" have been identified in cows, whippets, and humans; in each case the result is a dramatic increase in muscle mass. Further, the gene has been shown to be conserved in invertebrates, including many fish species. Follistatin is being studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin (aka GDF-8, a TGF superfamily member) which inhibits excessive muscle growth. Lee and McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in greatly increased muscle mass. In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength. This research paves the way for human clinical trials, which are hoped to begin in the summer of 2010 on Inclusion body myositis.'
A study has also shown that increased levels of follistatin, by leading to increased muscle mass of certain core muscular groups, can increase life expectancy in cases of spinal muscular atrophy (SMA) in animal models.
TMA member: Can you comment on the efficacy (both short and long term) of this type of gene therapy for a progressive disease like IBM versus other muscular diseases or injuries?
Drs. Mendell and Kaspar:In both rodents and non-human primates, the timing of the muscle enhancement and strength increase was nearly identical. This included studies in rodent models of muscle degeneration. The good thing is that the muscle enhancement persisted for long periods of time.
TMA member: Will medications like methotrexate need to be ceased for some period of time in order to participate in the trial?
Drs. Mendell and Kaspar:We will discuss this with the FDA, The likely answer is yes, to cease other medications for a period of time during the trial.
TMA member: The macaques did not have a degenerative muscle disease and I'd like to understand how confident you are that this would work on people with the disease and why.
Drs. Mendell and Kaspar:We have performed studies in mice that have degenerative muscle disease, and the therapy was beneficial in these animals; that is, we enhanced muscle mass and strength, and slowed the degenerative process. Our studies on monkeys were the next development to evaluate efficacy and safety. We are encouraged by both the rodent and monkey studies.
TMA member: If the therapy is successful, will it benefit all IBM patients regardless of how long they have had the disease
Drs. Mendell and Kaspar:We would certainly want to test this question in our clinical development.
TMA member: What specific disease(s) will be studied in the clinical trial? Will it be IBM, DMD, or something else?
Drs. Mendell and Kaspar:We are focusing the first trial on sporadic IBM. If successful, we would consider moving into additional muscle diseases.
TMA member: Might this gene therapy relieve many of the symptoms of IBM, soreness, weakness, tiredness, imbalance, Etc.
Drs. Mendell and Kaspar:We believe that Follistatin therapy will indeed increase and enhance strength, which likely will help with the symptoms you mentioned. Another benefit is that follistatin is anti-inflammatory, and we believe this would be beneficial in IBM.
TMA member: The clinical trial for monkeys focused on the quadriceps muscles. Do you anticipate that the therapy could also be effective on other muscle groups affected by IBM?
Drs. Mendell and Kaspar:Yes, we saw the greatest effects in the injected quadriceps, but also other benefit on other muscle groups, such as other leg muscles and arms.
TMA member: After the trial is complete and successful, will the patient receive injections in other weakened muscles like the arms?
Drs. Mendell and Kaspar:At this time, there would be no additional injections on patients that received the therapy. However, we anticipate that thigh injections will also have some effects on other skeletal muscles, such as the arms.
TMA member: Will the injection spread to other muscles in the body?
Drs. Mendell and Kaspar:The greatest effects will be in the local treated muscles (quadriceps) However in our studies, we did show some increase in other skeletal muscles. However, the greatest effects were in the thigh muscles (injected muscles).
TMA member: How much muscle do you need to have in your legs in order for you to be able to be in a trial, also the same question for hands and arms?
Drs. Mendell and Kaspar:The first trial is in the legs. The FDA will help make the decision about who can enroll. We will be checking with them as we get close to finishing the toxicology study.
TMA member: I have IBM for at least 15 years. I work out in a gym for about an hour every morning, using resistance machines and balance exercises. When I tell this to my neurologist and internist I get a shrug of the shoulders and told to keep it up as it cannot hurt me. No encouragement. In your work do you exercise the animals and if yes, what are the results.
Drs. Mendell and Kaspar:There are no animal models for IBM that simulate what patients have. We don't know the effects of exercise on the condition. I think as long as you keep active and exercise does not hurt you, then keep it up.
TMA member: Is it possible to expand the phase 1 trial since the NIH received the $5B in grants announced in October?
Drs. Mendell and Kaspar:Unfortunately, the $5B is unrelated to our trial. We do need additional funds and we are trying to raise them.
TMA member: Have you established the inclusion/exclusion criteria yet for the phase 1 trial? And if so, how are the selections made if you have more people interested than spaces available?
Drs. Mendell and Kaspar:The first trial requirements will be determined by the FDA. There will be 6-9 patients in the first trial. If we are successful other trials will begin shortly thereafter.
TMA member: Has this gene therapy the potential of also helping IBM patients that are advanced in their disease, e.g. wheel chair bound?
Drs. Mendell and Kaspar:We are not sure about this at the current time. We will have to test the capability and this will be part of the clinical trials program.
TMA member: If phase I of the clinical trials goes as well as we all hope, how soon could phase II (presumably with more patients) realistically begin?
Drs. Mendell and Kaspar:This will be an FDA decision but I would expect this to occur in one year after treatment begins.
TMA member: What has happened with the Limb Girdle Muscular Distrophy patients who were treated earlier this year.
Drs. Mendell and Kaspar:We have had a successful and safe treatment trial. Remember however this was a foot muscle and not the thigh muscle we will be treating in IBM.
TMA member: Can gene therapy result in any new muscle fibers or does it only increase the size of existing fibers.
Drs. Mendell and Kaspar:There is theoretical reason to believe it might do both but our study is targeted at increasing the size of existing muscle.
TMA member: What about myostatin? Is it safe to take and does it really work?
Drs. Mendell and Kaspar:So you wouldn't want to take myostatin as muscles would shrink, Myostatin is a negative regulator of muscle mass. Instead, an inhibitor of myostatin would be advantageous. While there are advertisements on the internet for these inhibitors, none have shown to work and are likely scams, and likely not safe. That is why the FDA so closely monitors drug development for safety.
TMA member: I realize that this therapy is for IBM, but was curious as to how it would work for patients with polymyositis.
Drs. Mendell and Kaspar:We cannot say at present whether this will work for PM. We need to do the trial first in IBM. If successful in this condition we will consider other diseases like PM. DM and PM are very complicated because of the immune response. We will start with IBM and move to other diseases if we are successful.
TMA member: Since researchers can't agree on a cause for IBM (degenerative or auto immune) at which pathway would gene therapy be directed? Given the age of IBMers can gene therapy rejuvenate skeletal muscle?
Drs. Mendell and Kaspar:This gene therapy introduces the Follistatin gene into patients. Follistatin increases muscle mass and strength. It also has anti-inflammatory responses, which we believe would be a further benefit for IBM. Our results show that this therapy increases and enhances existing muscles rather than creating new muscles, but we are currently investigating this in further studies.
TMA member: Are you optimistic that this gene therapy might also be beneficial for hIBM (hereditary inclusion body myopathy) patients as well? Would clinical trial seek to include hIBM patients?
Drs. Mendell and Kaspar:We have reason to believe that this will help multiple muscle diseases including hIBM, but currently we only have permission from FDA to do sIBM. If successful there, we would certainly move forward with other muscle disorders, including hIBM.
TMA member: Will this gene therapy affect only weak muscle or normal muscle as well?
Drs. Mendell and Kaspar:We plan to do gene therapy on weak muscles in IBM. The FDA would frown on any other approach.
Bob Goldberg, TMA: I wish we could continue the discussion, but we want to respect the time of Drs. Mendell and Kaspar. This is a very exciting development offering hope to many of those with myositis. We wish Drs. Mendell and Kaspar the best in moving this forward, and we will be sharing with all TMA members new developments as they happen.
Thank you to all who participated and a special thanks to Drs. Mendell and Kaspar.
Drs. Mendell and Kaspar:Thank you all for the questions and the opportunity to answer. We will try to answer as many of the questions in the near future and TMA will help email our responses. We will continue to work as hard as we can to move this potential effective therapy forward. We will keep TMA updated on our progress.
With Best Wishes, Jerry Mendell and Brian Kaspar


Krivickas LS, Walsh R, Amato AA.

Myostatin inhibitors are being investigated as treatments for myopathies. We assessed single muscle fiber contractile properties before and after 6 months of study drug in 6 patients with facioscapulohumeral, Becker, and limb-girdle muscular dystrophy. Five of the patients received MYO-029, a myostatin inhibitor, and 1 received placebo. The chemically skinned single muscle fiber preparation was used to measure single fiber force, specific force, maximum unloaded shortening velocity, power, and specific power in type I and IIa fibers from each subject. In 4 of 5 patients who received MYO-029, improvement was seen in single muscle fiber contractile properties; thus, there may be a beneficial effect of myostatin inhibition on muscle physiology at the cellular level. No improvement was seen in the patient who received placebo. This finding may be clinically relevant in spite of the fact that quantitative muscle strength measurements in our patients did not improve. Further studies of myostatin inhibition as a treatment for muscular dystrophy are warranted, and single muscle fiber contractile studies are a useful assay for muscle function at the cellular level.
Here are several excerpts taken from the article.
The key finding of this study is that MYO-029, a neutralizing antibody to myostatin, improved the single muscle fiber contractile properties in 4 of 5 patients with muscular dystrophy who received MYO- 029.
The efficacy of myostatin inhibition is most likely disease-specific and may also be dependent upon the stage of the disease during which therapy is provided.
The results of this small case series of patients treated with a myostatin inhibitor are promising. Although the larger study of MYO-02932 did not demonstrate improvement in whole muscle size, strength, or function, there appears to be some beneficial effect of the drug at the cellular level, and it may be dose-dependent. Four of the 5 patients receiving drug received the lowest dose given in the larger study,32 so it is impressive that improvement in specific force and power was seen even at these low doses. The patients enrolled in this study were adults with chronic disease; greater benefits might be achieved by inhibiting myostatin at a younger age, and thus at an earlier stage in the disease process. Further study of myostatin inhibition in patients with muscular dystrophy is warranted, and single muscle fiber contractile studies provide a useful assay for the effect of treatment on physiology at the cellular level.


Rodino-Klapac, et al, 2009

"The antiinflammatory effects of follistatin that accompany AAV-mediated follistatin gene therapy are also of potential benefit to certain patient groups such as those with sporadic inclusion body myositis." (Rodino-Klapac, et al, 2009). This research group expanded studies from mice to the cynamologous macaque where results "have been remarkably successful." The authors conclude that the stage is set for clinical trials in humans. No adverse effects have been uncovered. The authors concluded that the anti-inflammatory effects of follistatin may also contribute to efforts to treat sporadic inclusion body myositis.



Myostatin is a protein that is found in high concentrations in muscles where it normally acts to limit muscle growth. Myostatin, formerly known as Growth and Differentiation Factor 8 (GDF-8), is a growth factor that acts as a signaling molecule between cells. Manufactured in skeletal muscle, myostatin circulates in the blood and lymph, where it attaches to receptors on the membranes of other muscle cells. Myostatin is thought to act to limit the development of muscle stem cells and thus act to inhibit muscle growth. In 1997, a group from Johns Hopkins demonstrated that myostatin production is controlled by a gene and that by knocking this gene out, they were able to suppress myostatin levels leading to about a doubling of muscle production in normal mice (McPherron, et al, 1997). As research continued, researchers eventually discovered a child in Germany with mutations to both copies of his myostatin producing gene leading to the phenotype of unusually large muscle development. In addition, a mutation in cattle has been exploited through selective breeding leading to the development of myostatin suppressed livestock having abnormally large muscle mass.


Myostatin levels vary throughout the lifespan, during development levels are normally suppressed allowing more growth, whereas in adulthood, myostatin production reaches its maximum.

Myostatin is inhibited by another protein called follistatin. In the human, the gene controlling follistatin production has been discovered allowing research on the potential control of myostatin production.



Haidet, AM, Rizo L, Handy C, et al (2008). Long term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc. Natl. Acad. Sci. U.S.A. 105 (11): 4318 22. doi:10.1073/pnas.0709144105. PubMed Link

Krivickas LS, Walsh R, Amato AA. Single muscle fiber contractile properties in adults with muscular dystrophy treated with MYO-029. Muscle Nerve. 2009 Jan;39(1):3-9. PubMed Link

McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90. PMID 9139826

Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009 Feb 10;39(3):283-296. PubMed Link