FightSMA’s Research Legacy

By Alex E. MacKenzie, MD, PhD

Professor, Pediatrics and Biochemistry, University of Ottawa
Director, Children’s Hospital of Eastern Ontario Research Institute

>>> Jump down the page to “The Path Forward”

I’m Alex MacKenzie. I’m a pediatrician and geneticist working in Ottawa, Canada. For the last twenty years I’ve had the honor and privilege of working on spinal muscular atrophy, SMA, and I’ve had the honor and privilege of working with the organization FightSMA. Over the past two decades, the root from the first genetic studies mapping the SMA gene to chromosome 5, to our present situation, so filled with therapeutic promise, has been marked by many important steps forward. FightSMA has had an active role throughout this time enabling many of these critical advances, often funding critical seed moneys allowing larger research endeavors to go forward.

Back in 1991 when the SMA gene was first cloned by the laboratory of Conrad Gilliam with Judith Melki, FightSMA became initially involved, giving to the Conrad Gilliam lab a DNA sequencer. Using this DNA sequencer, Conrad Gilliam’s lab, following their mapping in 1991, published very important work, what we call mapping work, showing exactly the locale of where the SMA gene was located. Although theirs was not the lab that ultimately cloned the gene, that was Judith Melki’s Paris lab that did this, the work funded by FightSMA was absolutely critical in the isolation of the gene. After you isolate a gene for a genetic disorder, it then becomes an important question of how the gene works and how one goes about studying new treatments. Once again FightSMA was there funding the generation of what they call “animal models,” taking the genetic defect and putting it in a different species. Thus, they were the first to support the funding of Judith Melki, the creation of a novel SMA mouse model as well as the flatworm, C. Elegans (M. Lorson), the zebrafish (Burghes), and more recently pioneering development of a swine model, a pig model of SMA taking place in Missouri. This is going to be important for studying new treatments, isolating tissue, and understanding how the disease works.

In SMA, there’s also the presence of another gene besides the SMN1 gene which causes it, a second gene called SMN2 which makes less of the SMN protein but still makes some of it, and if we can learn how to turn it up, it can be a therapy. FightSMA has been a pioneer in funding labs that identify novel, so-called, SMN2 inducers — amino glycocides, p-38 inhibitors — called by a variety of names. The work taking place in the labs of Dr. Chris Lorson in Missouri, Dr. Arthur Burghes in Ohio, my laboratory, they really have been important in identifying novel classes of potential SMN therapies. In 1996, FightSMA co-hosted with NIH a meeting into which they invited Adrian Krainer, a world leader in something known as RNA-splicing. This really brought Dr. Krainer over into the world of SMA and he’s been an important researcher in the field ever since, identifying novel means of therapy. An assay developed by the laboratory of Elliot Androphy in Boston, funded once again by FightSMA, has been an important first step in the world’s largest high throughput screen of over a million compounds for SMN2 inducers.

In addition to a drug therapy for FightSMA, using pharmacologic agents, one also talks about gene therapy, where one identifies a snippet of corrected DNA and introduces it into the cells. Once again, FightSMA was there, first funding Arthur Burghes’ lab in Columbus, Ohio as well as SMA work at Oxford BioMedica in the UK under Drs. Nicholas Mazarakis and Mimoun Azzouz. Their work showed the lenti-virus rescue of a severe SMA mouse model was really the first effective gene therapy ever published for SMA. Brian Kaspar, working in Columbus, Ohio, has based his work on some of the earlier lenti-virus and is really showing an exciting promise. In addition to the gene therapy, one can also talk about stem-cell work. Dr. Douglas Kerr, a pioneering stem-cell researcher formerly at Johns Hopkins has done important work showing initial promise for this approach, funded in part by FightSMA. It must be said that this approach, exciting as it is, still lies somewhat in the future. Finally, FightSMA has supported Dr. Nick Boulis, previously at the Cleveland Clinic and now at Emory in Georgia, studying how to actually administer stem cells to the spinal cord of primates.

So FightSMA has been very busy in basic research but they’re aware also that families who have children with SMA face day to day problems and worries. So the FightSMA research scope has incorporated other areas not just gene cloning and basic biochemistry. For example, it’s been long recognized that they have difficulties with the heart, both blood pressure and heart rhythm. FightSMA was the first to fund a study of the so-called autonomic system in the laboratory of John Bach in New Jersey. As well, how one treats infants and children from a respiratory standpoint has been a controversial area. Dr. Bach, working with Brian Weaver, has been a pioneer in this area, and FightSMA has really supported spreading this approach across the SMA community. That, plus the rational dietary approach for SMA have been topics for the Thriving with SMA panels which have been part of the FightSMA Annual Meeting.

Importantly, the first real rigorous, what we call, “placebo-control” trial for SMA was funded by FightSMA in the late 1990′s. Although Gabapentin was shown not to be effective in this case, it was the first template of how one does a clinical trial for SMA and has been used as a role model for others since then. Currently, the funding of a pre-symptomatic trial, that is to say giving the drug before the infant develops the symptoms of SMA, in the laboratory of Dr. Kathy Swoboda will be important because an anxiety with the SMA trials is, after the motor neurons are gone, it may be difficult to see a positive effect. In this case we’re going to be getting in there before the motor neurons are dying off.

In general, a theme of good citizenship is something that FightSMA strives for. Their supportive meetings, their Annual Family and Researcher Conferences in Washington, meetings such as the SMA Drug Summit, supporting the Standard of Care Statement, issued recently, and the SMA Patient Registry have all been part of their portfolio and important to all that we do. Common resources, things that can be generated by one lab but used by other labs, is another recurrent theme that FightSMA has tried to achieve. For example, the so-called SMN Elisa, the ability to actually measure levels of the SMN protein in a robust and high throughput manner enabling drug screens and pioneered in Glenn Morris’ lab in Wales, received seed money. Also, the dissemination of the iPS stem cells, discovered by Clive Svendsen and FightSMA science director Chris Lorson, which allows these cells to be spread among other laboratories, is another project supported by FightSMA.

One of the most exciting things with our SMA research is the unanticipated consequences for other disorders. Work in my laboratory at Children’s Hospital of Eastern Ontario, for example, has real application to a disorder known as Myotonic Dystrophy. Using techniques that we really discovered through our work on Spinal Muscular Atrophy, has identified what we think is an effective therapy for this really common form of muscular dystrophy.

I’d like to thank you for spending the last few minutes here with me. I invite you to spend some time here on for information on ongoing research projects, upcoming meetings, and general information are all available.

The Path Forward

So where are we today? Clearly there are questions that face a family with SMA. What’s the best diet for your child does it differ between type 1, type 2, and type 3? What’s the best respiratory intervention: when to start C-Pap, how to administer it? Orthopedic interventions are something we have not discussed. What is the appropriate operation? When should it be done? These are real central basic issues which face these families and ones that FightSMA hopes to resolve with you in the Thriving With SMA panels and with appropriate research funding.

There’s tremendous hope and optimism. The last two decades has seen enormous progress. We know the SMN1 Gene causes SMA, we know the protein that it makes is SMN, we know where it lives within the motor neuron, and we increasingly know what it does. Critically, we know that depressed levels of this SMN are what causes SMA and therefore, raising those levels back up again will be an appropriate treatment. There are two means of doing this which hold true promise we believe: one is the drug-induced of the so called SMN2 gene. Work funded by FightSMA as well as other agencies has shown a variety of drugs, some of them FDA approved, which does this robustly in the mouse model. The question is, which one, or which combination of drugs, do this best in the mouse model? And, therefore, which ones do we take forward in the clinical trials? We hope, working with other agencies and other researchers, to enable the benchmarking of these drugs, pharmacologic agents, identifying those that need to be trialed initially. Our hope is in the next three years this will be achieved. On the other hand, in addition to drug-induction of SMN there is gene therapy. FightSMA funded Lenti-Virus approach was really the pioneering work in gene therapy for SMA. Work by Dr. Brian Kasper and other pioneering research, funded by FightSMA, has shown that the gene vector known as AAV can replete or increase SMN levels dramatically in motor neurons, in mouse models, virtually curing the disease. The next questions are: Can this be done in primates and can enough of it be made? And, is this a safe approach? Thus on the one hand with drugs, on the other with gene therapy, the expectation is over the next three to five years a viable therapeutic solution will be identified. Of course, this relies upon the infrastructure for the clinical trials at present. Work that FightSMA and others have done so tirelessly and the SMA Treatment Acceleration Act will ensure that there is the appropriate infrastructure for clinical trials to take place. Finally, in a perfect world the ability to identify SMA in babies before they develop the symptoms would be a marvelous thing. Once again, there’s work occurring both in our center in Ottowa, as well as that of Tom Pryor where a newborn screening is being patented. It’s the hope that in the next 2-3 years, universal newborn screening for SMA will be a reality.

Thanks very much for spending the time with us here on the web, and I look forward to entertaining your further questions as well as joining you in the fight against SMA.

Special thanks to Metro Productions for the pro bono production of Dr. MacKenzie’s videos.