The following article contains items about: Duchenne and limb-girdle muscular dystrophies
Researchers supported by MDA and the National Institutes of Health say results of a gene therapy trial in three people with type 2D limb-girdle muscular dystrophy (LGMD) are the first to show promise beyond safety alone. This type of LGMD is due to a deficiency of the muscle protein alpha-sarcoglycan.
Neurologist Jerry Mendell, co-director of the MDA clinic and director of the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio, received MDA support to coordinate the study team, which announced its results online April 16, 2009, in Annals of Neurology.
Although the primary goal of the small trial was to establish the safety of intramuscular injection of the alpha-sarcoglycan gene into a foot muscle, the investigators also evaluated how long gene activity persisted in the muscle, the level of alpha-sarcoglycan protein produced from the gene, and the response of the immune system to the gene.
No adverse events, such as rejection of the therapy by the immune system, occurred during the trial, reassuring researchers of the likelihood that their approach is safe in people with this form of LGMD.
Moreover, all three trial participants produced four to five times the amount of alpha-sarcoglycan protein in the gene-injected foot muscle compared to the amount in the corresponding muscle on the other foot, which received a salt solution. This level of output from the transferred gene persisted at least until the date of the last evaluation, which was six weeks after injection in one participant, seven weeks in another, and 12 weeks in a third.
In each case, the alpha-sarcoglycan protein assumed its normal position in the membrane of the muscle fiber and restored the structure of a protein cluster that’s normally found at that location but is missing in muscles that lack alpha-sarcoglycan. The cluster is crucial to the integrity of the muscle fibers.
The response of the immune system to the transferred gene and its carrier, a viral shell, was brief and minimal in all cases and did not interfere with gene activity.
No improvement in function was expected from this direct injection into a very small area. A delivery method that reaches a large muscle area will be necessary to improve function, the researchers say.
They also note that the study has potential relevance for other muscle diseases and for diseases in which muscle tissue can be used to secrete therapeutic proteins into the bloodstream.
AVI BioPharma of Portland, Ore., has started the systemic (through the blood) delivery phase of its clinical trial of AVI4658 in Duchenne muscular dystrophy (DMD). The trial is being conducted in the United Kingdom.
In January, the company announced that this laboratory-engineered molecule was safe and well tolerated when injected directly into a foot muscle in boys with DMD. More importantly, the molecule led to production of dystrophin, the necessary muscle protein missing in DMD, in all trial participants.
AVI BioPharma said the systemic-delivery phase of the trial now under way will test the safety and efficacy of administering AVI4658 intravenously into 16 boys with DMD. Systemic delivery is expected to reach several muscles and potentially could improve strength and function.
The 12-week study is being conducted in London and Newcastle Upon Tyne, United Kingdom. Francesco Muntoni at Imperial College London, who has MDA support to conduct research in another muscle disease, is the principal investigator. Support for this trial comes from AVI BioPharma and the British Medical Research Council.
AVI4658, a so-called antisense compound, is designed to cause muscle cells to skip over an error in a region (exon) of the gene for the dystrophin protein (see “Success of exon skipping.”)
In its Feb. 19, 2009, press release, AVI said the earlier results and preclinical research suggest that “by skipping [exon 51], a truncated but functional form of the dystrophin protein is produced to ameliorate the disease process, potentially prolonging and improving the quality of life in these patients.”
A somewhat surprising result about moderate-dose, daily prednisone versus high-dose, weekend-only prednisone in boys with Duchenne muscular dystrophy (DMD) was obtained by a team of researchers from Children’s National Medical Center in Washington (CNMC) and the University of Pittsburgh.
The corticosteroid drug prednisone often is prescribed for boys with DMD because it has been shown to slow the decline of muscle strength.
The investigators found behavioral side effects associated with prednisone lessened over the course of a year in the daily prednisone group but stayed the same in the weekends-only prednisone group.
Twenty-eight boys with DMD were randomly assigned to receive 0.75 milligrams per kilogram of body weight of prednisone daily, while another 28 were randomly assigned to receive 10 milligrams per kilogram of prednisone weekly over two consecutive days (the weekend).
The investigators administered the Child Behavior Checklist (CBCL) rating scale at screening and after one, three, six, nine and 12 months.
Total behavioral problems at the start of the study were similar between the two treatment groups. One month into treatment, there were no changes in behavior within the weekend prednisone group and an improvement in total problems and attention in the daily prednisone group.
After a year, there were no significant differences within the weekend group. However, in the daily prednisone group, there were significant decreases in total problems, such as attention and aggression. The daily group also showed significantly fewer behavioral problems than the weekend group at one year.
At the 2008 AAN meeting, researchers announced analyses of other aspects of this study. At that time, they said the effects on maintenance of strength were similar between the daily and weekend prednisone dosing schedules, but that the time required to rise from the floor was better in the daily group.
Growth retardation, another predniosone side effect, was less severe in the weekend prednisone group. The weight gain side effect was the same in the two treatment groups after one year.