This story was updated Oct. 6, 2010.
Researchers, clinicians, pharmaceutical industry executives, and representatives from advocacy groups, including MDA, met in Washington Sept. 27-28, 2010, to discuss moving forward with antisense-based therapies for neuromuscular disease.
The conference focused on the potential for antisense development as a treatment for four diseases: amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), myotonic dystrophy (MMD) and spinal muscular atrophy (SMA).
Neurologist Valerie Cwik, MDA Medical Director and executive vice president for research, and Annie Kennedy, MDA Senior Vice President-Advocacy, represented MDA, which helped fund the meeting. Principal sponsors were the U.S. Food and Drug Administration (FDA) and the U.S. National Institutes of Health (NIH), although several attendees and speakers were from outside the United States, giving an international perspective to the proceedings.
Also participating were Anne Pariser, acting associate director for rare diseases at the FDA, and John Porter, program director, extramural research program, National Institute of Neurological Disorders and Stroke at NIH.
Antisense oligonucleotides, or AONs, are short strands of chemicals called "nucleotides" that are targeted to specific strands of RNA, the chemical step between DNA (genes) and protein synthesis.
The last several years have shown that the steps between RNA and protein synthesis in cells provide numerous opportunities for therapeutic intervention. In some genetic diseases, intervening at the RNA level may be easier, safer and/or more effective than adding DNA (gene therapy), adding proteins or blocking proteins that have been synthesized.
For more about antisense in general, see Defensive Action: Can toxic genes be blocked to treat disease?
Main topics of the meeting
The conferees heard presentations on and participated in subsequent discussions about the state of the science and technology in ALS, DMD, MMD and SMA; how to design laboratory (preclinical) studies in which to evaluate toxicity and effectiveness of antisense compounds; how to develop and use biomarkers, which in this context are biological indicators that can ascertain the effects of an antisense compound in a patient, preferably with minimal expense, pain or inconvenience; how to design clinical trials using antisense; and the role of patient registries in the effort to develop antisense technologies.
ALS and antisense
Current investigations of antisense technologies in ALS are aimed at stopping the synthesis of the SOD1 protein in ALS patients who have mutations in the SOD1 gene, a cause of familial ALS. An experimental drug called ISIS-SOD1-Rx, developed by Isis Pharmaceuticals, is in a clinical trial for people with familial ALS due to an SOD1 mutation. MDA has helped fund development of this AON and is supporting the current multicenter trial.
For more about ISIS-SOD1-Rx, see ALS SOD1 Trial: A 'Watershed Moment'.
DMD and antisense
In DMD, MDA has been supporting laboratory research on the use of AONs to bring about a phenomenon called "exon skipping," in which muscle fibers are coaxed to "skip" (ignore) certain parts of the RNA for the dystrophin gene and splice together the surrounding parts, ultimately leading to a functional dystrophin protein. A large variety of mutations in the dystrophin gene, which result in the loss of a functional dystrophin protein from muscle tissue, are the underlying cause of DMD.
For more about DMD and antisense/exon skipping, see:
MMD and antisense
In type 1 MMD, efforts are under way in laboratory studies, several of which have received MDA support, to develop antisense to block the interactions between expanded RNA in the DMPK gene and various proteins in the cell, particularly MBNL1. Abnormally expanded RNA in the DMPK gene is the underlying cause of type 1 MMD. There are no clinical trials testing antisense so far in this disease.
For more on antisense and MMD, see MMD Research: Bright Prospect.
SMA and antisense
In SMA, a large number of laboratory research projects, many of which have received MDA support, are looking into the possibility of using antisense to change the way RNA for the SMN protein is put together, or "spliced." Using AONs to mask certain parts of the SMN RNA made from the SMN2 gene has the potential to boost synthesis of functional SMN protein from this RNA.
Patients with SMA lack sufficient levels of functional SMN protein in their motor neurons because of mutations in a gene called SMN1. Genes known as SMN2, which SMA patients have, can produce small amounts of functional SMN protein, but it appears they can be coaxed to produce more through the use of AON technology. There are as yet no AON therapies being tested in clinical trials in SMA.
For more on antisense and SMA, see Antisense Treatment Restores Full-Length SMN in SMA Mice.
There was some clear optimism and excitement in the meeting room, brought about by a nearly unique combination of experts in various fields related to antisense development.
"There is a lot we can learn from each other," said Francesco Muntoni from University College London, in wrapping up the meeting. Muntoni said he is "quite enthusiastic" about the therapeutic possibilities of AONs but that one needs to keep a balanced view and even "be prepared for lack of success."
The scientific insights of the past decade have made possible what would not have been conceivable not too long ago: altering the processing of genetic information to treat genetic disease. On the other hand, scientific and practical obstacles to drug development using antisense remain.
Although the idea of "personalized" medicine — developing medications not just for specific diseases but for specific populations within those diseases or even for specific patients — has been met with enthusiasm by the public, there are significant obstacles to its achievement.
For example, the dystrophin gene, which is mutated in DMD, has 79 exons — regions of the gene that code for the dystrophin protein. Although there are mutation "hot spots" in the gene in and around exons 51 and 44, there are significant numbers of patients who won't be helped by AONs targeting these exons.
Whether pharmaceutical companies will develop drugs for what may be minuscule numbers of DMD patients remains to be seen, especially if a very high bar is set for approval of each AON.
If each AON targeting each exon has to go through the entire gamut of safety and effectiveness hurdles normally mandated for approval of a new drug, it may not be feasible to develop AONs for all or even nearly all DMD patients.
The FDA does not yet know what its regulatory bar will be for each AON. However, at this point, safety and efficacy of one AON cannot be assumed to apply to other AONs if their targets are different, even if they are targeting the same gene.
In addition, as pointed out by Jerry Mendell of Nationwide Children's Hospital, the immune system in some boys with DMD has been shown to reject newly synthesized dystrophin in a recent dystrophin gene therapy trial, raising the question of whether newly synthesized dystrophin resulting from an antisense treatment might not also elicit an immune response, at least in some patients. Such questions and any possible solutions to them remain to be answered.
Delivery of AONs, particularly to the central nervous system, which will probably be necessary in SMA and ALS, also poses some special hurdles, which will need to be addressed. ISIS-SOD1-Rx is being delivered directly into the spinal fluid of ALS patients via a catheter and an external pump. This method is likely to be safe, as it's been used with other drugs, but it isn't yet known whether it will be effective in treating disorders of the central nervous system with AONs.
Other challenges also were extensively discussed, among them developing and maintaining detailed patient registries from which to identify potential AON trial participants; developing practical ways to measure the effects of an AON without performing multiple tissue biopsies; and conducting trials across wide geographic areas or even across national boundaries, which may be necessary for rare diseases.
Although the conference was open to the public via webcast, the webcast will not be archived online, said NIH's John Porter. NIH is expected to post a summary of the proceedings on its website at a later date, and MDA will continue to keep readers informed about developments in this strategy.
Editor's note 10/6/10:The October 2010 neuromuscular disease research podcast from Nationwide Children's Hospital in Columbus, Ohio, is a 15-minute interview about antisense strategies for neuromuscular disease with molecular geneticist Annemieke Aartsma-Rus at Leiden University Medical Center in the Netherlands. You can listen to this very informative podcast atThis Month in Muscular Dystrophy.