Mice with a disease resembling spinal-bulbar muscular atrophy (SBMA, or Kennedy disease) that were treated with a compound based on insulin-like growth factor 1 (IGF1) had better motor function, slower weight loss, healthier muscles and longer survival time than mice that received an inactive substance, an MDA-supported research team has reported.
The research team also found that SBMA mice that overproduce a muscle-specific form of IGF1 have a milder disease course than mice that produce less of the protein.
The new findings suggest that IGF1 potentially may be effective in ameliorating the disease via at least two mechanisms:
The research team reported its findings online Aug. 29, 2012, in Molecular Medicine. To read the full report, see IGF-1 Administration Ameliorates Disease Manifestations in a Mouse Model of Spinal and Bulbar Muscular Atrophy. MDA supported Maria Pennuto at the Italian Institute of Technology in Genoa, Italy.
The researchers treated SBMA mice with a compound called mecasermin rinfabate (brand name Iplex), which is a combination of IGF1 and IGF1 binding protein 3. (The binding protein helps IGF1 last longer in the body.)
Male mice were randomly assigned to receive abdominal injections of the IGF1-based compound at a daily dose of 15 milligrams per kilogram of body weight, or an inactive substance. To mimic the typical clinical setting (in which a diagnosis of SBMA occurs after symptoms appear) the researchers began injections when the mice were 10 weeks old, after disease onset, and continued through 20 weeks.
The researchers evaluated body weight, motor function and survival in the mice. They found that, when compared to the placebo-treated mice, those treated with IGF1 had:
In addition, the researchers found that the IGF1-treated mice had markedly reduced muscle shrinkage (atrophy) and degeneration.
The study results provide a basis for further study of IGF1-based compounds as potential therapies for people with SBMA.
Iplex, which was developed by Richmond, Va., biopharmaceutical company Insmed, was approved by the U.S. Food and Drug Administration in 2005 for treatment of children with growth failure due to severe deficiency of IGF1. It has been tested in other diseases, including amyotrophic lateral sclerosis (ALS) and type 1 myotonic muscular dystrophy (MMD1).
Insmed announced in March 2009 that it would work with the FDA to develop a clinical trial of Iplex in people with ALS. (See FDA Allows Formal Testing of Iplex in ALS.) There is no evidence that the drug is effective against ALS, but it has been available for use by ALS patients in other countries, particularly Italy, and data have suggested that the compound is reasonably safe.
In June 2009, Insmed announced that the drug had failed to improve muscle function, strength or endurance in adults with MMD1, although it did improve the ability of cells to respond to insulin in some trial participants. (See Iplex Shows Limited Benefit in MMD1.)
Results from another study, published in January 2011, showed that treatment with Iplex in 15 people with moderate MMD1 was well tolerated and associated with increased lean body mass and improvement in metabolism. However, it did not increase muscle strength or function.
To learn more, read the full report: An Open-Label Trial of Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-1/rhIGFBP-3) in Myotonic Dystrophy Type 1.
SBMA may be a better candidate for IGF1-based therapies than ALS or MMD1, because in addition to the nonspecific benefits it confers on muscle and nerve survival, it changes the behavior of the abnormal AR protein that underlies SBMA.