Rescuing SBMA-Affected Muscles

A protein known as insulin-like growth factor 1 (IGF1) may provide a new lead in the treatment of spinal-bulbar muscular atrophy (SBMA), also known as Kennedy disease.

A multinational team coordinated by MDA research grantee Maria Pennuto at the Italian Institute of Technology in Genoa, has found that having extra IGF1 genes seems to improve muscle strength and function in mice bred to have an SBMA-like disease.

The team, which published its findings Aug. 13, 2009, in the journal Neuron, also included MDA-supported J. Paul Taylor at St. Jude Children's Research Hospital in Memphis, Tenn.

About these experiments

The researchers bred one group of mice with an SBMA-causing genetic mutation and an SBMA-like disease, and they bred another group of mice with this mutation and extra IGF1 genes. These genes caused them to produce a muscle-specific type of IGF1 in their skeletal muscles (and not in other tissues).

Spinal-bulbar muscular atrophy (SBMA) affects men almost exclusively, usually begins in middle age, and leads to weakness of the voluntary muscles of the face, mouth, throat, limbs and trunk.

When the investigators compared the two groups, they found the SBMA mice that received the extra IGF1 genes fared better than those without the extra genes on a number of measures, including having better motor function, increased muscle mass and strength, and a longer survival time.

The IGF1-treated mice also showed increased activity and more interest in exploring their surroundings.

"Altogether, these results show that IGF1 reduces muscle weakness and improves motor function in SBMA mice," the researchers say.

Microscopic and biochemical analyses of tissue from the spinal cord and muscles of the treated mice showed the cells were closer to normal than those of untreated mice.

About SBMA

In the 1990s, MDA-supported researchers determined that SBMA is caused by a mutation in the gene for the androgen receptor protein, which is involved in processing of the male hormone androgen.

The disease affects males almost exclusively and usually begins between ages 30 and 50.

Motor neurons in the brainstem, which control the muscles of the face, mouth and throat (the "bulbar" muscles), are lost, as are motor neurons in the spinal cord, which control voluntary muscles throughout the body.

Weakness and even paralysis of the facial muscles, difficulty chewing, swallowing and speaking, and loss of strength and mobility result. Some loss of androgen function can also occur, causing breast development and reduced fertility in some men.

In human and mouse SBMA, extra DNA abnormally enlarges the androgen receptor gene. The type of mutation involved is called a "triplet repeat expansion." The "triplet" in SBMA consists of the DNA chemicals cytosine, adenine and guanine, or CAG. In SBMA, this sequence is repeated many more times than normal.

A cellular hallmark of SBMA is the presence of clumps of androgen receptor protein molecules in muscle and nerve cells. Until recently, it was believed that the main problem in SBMA was the result of damage to muscle-controlling motor neurons rather than direct damage to muscle cells themselves. However, it's now increasingly believed that direct damage to muscle from mutated androgen receptor genes also plays a role.

About IGF1

IGF1 belongs to a class of proteins known as trophic ("nourishing") factors. Various IGF1-based compounds have been tried in the last decade to treat muscle and nerve diseases. Most recently, the experimental drug Iplex, based on IGF1 and another protein, has been tried in myotonic dystrophy. Earlier, an IGF1-based drug called Myotrophin was tried in amyotrophic lateral sclerosis (ALS). Neither drug was judged beneficial in improving the course of either disease, although each was found to be safe. (Also, neither of these utilized the muscle form of IGF1 that was used in these experiments.)

The rationale for using IGF1 in ALS and myotonic dystrophy was less specific than it is for SBMA. In the first two cases, it was hoped that IGF1 would act as a general muscle-building agent.

By contrast, the role of muscle-specific IGF1 in alleviating the signs and symptoms of SBMA in mice appears to be related to its direct effects on the androgen receptor protein. In the SBMA-affected cells, IGF1 caused the abnormal, toxic androgen receptor protein molecules to undergo destruction through a specific cellular pathway, reducing clumping of the protein in muscle cells.

The scientists say they think the beneficial effects on motor neurons in the mice may be secondary to the improved health of the muscles and/or to the transport of IGF1 from muscle fibers to motor neurons.

The benefit to motor neurons from therapy aimed only at muscle tissue was somewhat unexpected. It provides an added incentive for therapeutic development using IGF1 in SBMA, as muscles are more accessible than motor neurons.

Meaning for patients

The results of this study by MDA-supported Maria Pennuto and colleagues provide a new strategy that can be explored for the treatment of human SBMA, using a compound that's already been the subject of much investigation.

Although IGF1 hasn't so far been effective in neuromuscular disease treatment in humans, these new findings are encouraging, because the mechanism by which the protein improved cellular health in these mice is unique to SBMA.

Next steps would need to include a biotechnology or pharmaceutical company's willingness to test a compound based on IGF1 for SBMA.

MDA's Venture Philanthropy program encourages companies to apply for MDA funding for this type of drug development.

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