In the words of Audrey Lewis, Executive Director of Families of SMA, "…isn’t this year’s meeting incredible?" No truer words were spoken. The 4th annual meeting of the North American/International Spinal Muscular Atrophy Research and Clinical Group was held in St. Louis on June 9th and 10th. There were more than 60 participants representing research groups throughout North America, Europe and as far a field as Taiwan. The first day covered 16 oral presentations reporting recent progress in the areas of SMN function, animal models and therapeutic strategies. The second day was devoted to a round table discussion of future directions, a discussion of protein delivery and animal testing strategies as well as an overview of current and future clinical trials. In the following, I will summarize some of the recent advances emphasizing the major milestones that have been met during the past year.

Research on SMN function since its initial discovery by Dr. Judith Melki’s team has implicated SMN in the assembly and regeneration of a complex involved in RNA splicing, an essential function required in all cell types. To fulfill this role, SMN must interact with a number of proteins and the resulting SMN complex must migrate between the cytoplasm and nucleus of a cell. Recent work has led to the characterization of a number of proteins that are found within the large SMN complex. This work is significant for several reasons. First, analysis of this complex will provide a better understanding of SMN function. Second, the existence of isoforms of these proteins may explain, in part, the variable clinical presentation of 5q-SMA or alternatively, may help to identify potential candidate genes for non-5q SMA. Third, this work may suggest additional targets for therapeutic intervention. Many of the interacting domains have been mapped and a preliminary 3D structure for SMN was proposed. 

As many of you are aware, a number of new mouse models have been completed during the past year and these SMA mice are much more useful than the original ‘knockout’ mouse prepared by Dr. Michael Sendtner’s group in 1997. As you may recall, the ‘knockout’ animal lacks mouse Smn and dies very early during embryonic development, precluding access to live born SMA mice. Two different strategies have been used to circumvent this problem. First, the groups of Drs. Arthur Burghes & Michael Sendtner and Dr. Hung Li’s team have produced mice that lack mouse Smn but have the human SMN2 (centromeric SMN) gene. These live born mice have SMA and loss of motor neurons appears to occur after birth. Significantly, the severity of the disease is dependent upon the number of SMN2 gene copies introduced. Mice with 8 SMN2 genes do not have SMA indicating that large amounts of SMN2 can reverse the muscle atrophy and motor neuron degeneration caused by SMN deficiency. In addition, a 3 to 4 fold increase in SMN2 protein is not toxic to the mice. 

Second, Dr. Judith Melki’s team have generated mice that lack Smn exon 7 in motor neuron cells only and mice that lack Smn exon 7 in muscle cells only. In both cases, these mice survive the first few weeks of life and have SMA. As is the case for the first series of animals mentioned above, motor neuron loss appears to be a late manifestation of SMA disease. In addition, Dr. Melki’s work suggests that SMA is caused by a defect in both motor neurons and muscle. Live born SMA mice will provide an invaluable resource for testing a number of different therapeutic strategies before their introduction into clinical trials.

Therapeutic strategies discussed during the two day meeting included drug discovery using high throughput screens, stem cell therapy and protein delivery. Families of SMA have signed a contract with Aurora (San Diego) to conduct a high throughput drug screen aimed at identifying compounds that can either increase SMN2 gene expression or enhance retention of exon 7 in RNA produced by the SMN2 gene. This work is being done in close collaboration with research laboratories that are providing valuable tools as well as testing assays that can be used to determine if a specific compound can affect either expression or splicing of SMN2. Initial screens of over 500,000 compounds are expected to take 1 to 1 1/2 years. There is great hope that specific lead drugs can be identified within the next two years. Given that animal models already exist, once these compounds are identified, they will be made available to researchers for immediate testing in SMA mice. 

Dr. Doug Kerr presented recent work on stem cell therapy and while this work is very preliminary, there is hope that this approach may provide a viable alternative. Finally, studies designed to find ways to deliver SMN protein to cells indicate that this approach is extremely difficult with respect to targeting and stability of the protein. It is as yet unclear whether this strategy will be useful but on-going experiments should resolve this debate.

Several clinical studies are near completion and NIH has recently awarded monies for a three-year multi-centre clinical trial that will be directed by Dr. Susan Iannocone. The first phase of this study will be to identify valid and reliable outcome measures that can be used to test the efficacy of a given therapy. Great care will be taken to minimize variability in outcome measures within and between the five participating centres. Administration of a drug or other therapy will only commence in the final phase of this study. While a SMA-specific drug is not currently available, there is hope that such a drug will be forthcoming as a result of a number of high throughput screens in progress. Nonetheless, it should be stressed that participation in these studies is extremely important because the initial drug-free phases will help establish a functional network and appropriate study designs for the drug-testing phase once a SMA-specific drug becomes available. 

While great strides forward have been made, we still have further to go. We do not yet understand why motor neurons and muscle are the cell types most affected by the loss of SMN1. What is the function of SMN in motor neurons and muscle and by what mechanism does loss of SMN result in neurodegeneration and muscle atrophy? Are motor neurons and muscle specifically affected because they need more SMN1 or does SMN1 carry out additional tasks that are unique to muscle and motor neurons? A number of strategies are currently being explored to answer these questions. As mentioned above, a number of animal models have already been engineered and many more are expected to become available during the next year. Characterization of these models is in its early stages. More sophisticated analyses are currently underway which will hopefully provide a better understanding of the pathophysiology of SMA. Together this research will allow us to identify specific and non-specific targets for the treatment of SMA. These include targets that can effect SMN2 gene expression or stability of existing motor units. Because it is not yet clear whether a single or multiple therapeutic intervention will be required to efficiently treat SMA, a number of different strategies must be explored. Much of our current energy will be invested in high throughput screens aimed at identifying compounds that will increase the amount of available full-length SMN protein. A number of such screens are underway and this competition is healthy. Identification of similar types of compounds will serve to validate and replicate data between laboratories thereby pinpointing which compounds are most likely to succeed. While protein delivery may not provide a realistic therapy for SMA, one cannot exclude the possibility of gene replacement therapy necessitating studies aimed at identifying the most useful targeting vectors, determining the safety of such vectors as well as the treatment regimen required to achieve a positive outcome. Clearly, the utility of stem cell therapy must be explored. By following multiple avenues, there is no doubt that valid, safe and efficient strategies will be identified in the foreseeable future.

As always, on behalf of the participants, I would like to thank Families of SMA and the organizers of this year’s meeting for this opportunity to meet and exchange information about our recent progress and future goals in such a hospitable environment. In large part, it is the families that motivate us to accelerate the pace of our research endeavours. The gauntlet has been laid down; we expect to have a number of compounds available for testing in SMA models within the next two years. FDA has assured us that should interesting compounds present themselves, they will do everything in their power to facilitate transfer to clinical trials while maintaining stringent criteria with respect to safety. Clearly, the arrival of the year 2000 brings with it much hope for significant advances in SMA research during the next decade. 
              

From FSMA Direction, Summer 2000
Posted August  2000