Spinal Muscular Atrophy Research

An Informed and Focused Strategy

FightSMA works intimately with leading spinal muscular atrophy (SMA) scientists from around the world, helping to articulate and support a focused research strategy. That strategy identifies the most promising SMA research opportunities, coordinates the efforts of numerous laboratories, and makes the most effective use possible of precious financial resources.

The FightSMA research strategy is tightly aligned with the approach articulated by leading SMA scientists in their Spring 2003 “Open Letter of Scientists to the Director of the National Institutes of Health on Spinal Muscular Atrophy.” That letter reads, in part:

“Our most educated expectation is that with NIH funding of $20 to $30 million annually, an effective therapy for spinal muscular atrophy can be achieved in the near term of five years or less.”

This remarkable and dramatic conviction drives organizations like FightSMA to increase efforts to secure higher levels of funding than are currently in place and is the defining coordinates for the FightSMA research strategy.

Toward the end, FightSMA works with other family groups to encourage the federal government to increase its financial support for SMA research. FightSMA organizes fundraising events, conducts mailings, and solicits support from foundations, corporations, and individuals.

It is the fervent hope of all children fighting SMA and of the parents, families, and friends of those children that more individuals will learn of this fight and support it with all the financial assistance they possibly can. It is a worthy and noble fight. And a victory is near.

The Research Strategy: A Closer Look

The FightSMA research strategy takes advantage of the remarkable science revelations that the SMA research community has seen since the 1995 discovery of the gene that is responsible for SMA.

In SMA, a vital gene called the “survivor motor neuron,” (“SMN”), a gene located on Chromosome No. 5 is missing. In the absence of that gene, the vital SMN protein, which is necessary for muscle strength, is in insufficient supply. Without that protein, the motor neurons die off and muscles that depend on the motor neurons atrophy and waste away. In the most severe cases of SMA, infants generally die by their second birthday. In other less severe cases, the disease is crippling and frequently life-threatening.

The tremendous potential for treatment lies in the unusual nature of the SMN gene. Even though the key SMN1 gene is deleted, there is a second “copy” gene, the SMN2 gene, that continues to produce limited quantities of the SMN protein.

The FightSMA research strategy attacks SMA on six tracks:

  1. Trick the remaining SMN2 gene into producing more protein.
  2. Replace the missing gene.
  3. Replace the protein.
  4. Find a small molecule substitute.
  5. Administer protective or growth-enhancing agents.
  6. Grow new motor neurons from stem cells.

Upregulation: Trick the Gene.

The “gene” referred to here is the “SMN2″ gene. This is the “spare tire” gene that remains, even though the critical “SMN1″ gene is deleted. The SMN2 gene continues to produce a limited amount of the SMN protein which is vital for muscle strength. SMN protein has been found to play a critical role in RNA splicing in motor neurons, and is therefore critical to motor neuron health and survival. The job, then, is to upregulate the SMN2 gene, that is, strengthen it do a better job than it is doing.

There exists in all SMA individuals, at least one copy of the SMN2 gene (formerly known as SMNcen). SMN2 is not completely deficient in making full-length SMN transcript and protein, thus the presence of SMN2 partially compensates for the SMN1 deletion. SMN2 is present in a variable number on Chromosome 5 and the number of SMN2 genes is higher in mild cases of SMA than in infants with severe SMA. The induction of SMN2 to make more SMN is clearly a promising therapeutic approach. Thus, the goal is the identification of a small molecule which via transcriptional upregulation of SMN2, modulation of SMN2 splicing, stabilization of SMN2 transcript, upregulation of SMN translation, or stabilization of SMN protein results in a meaningful increase of intracellular SMN protein.

A second candidate gene for activation is NAIP; many children with Type I SMA and most with Type II and Type II have non-mutated copies of NAIP. NAIP has been shown to be inducible, expressed in the motor neurons and to confer cytoprotection; consequently its upregulation may attenuate the natural history of SMA.

Ongoing research studies have provided leads on compounds which may increase the influence of this second copy of SMN (“SMN2″). Severity of the disease corresponds closely to levels of SMN protein, and therefore, upregulation of this second copy should mitigate the effects of the disease.

This is the program that is the farthest along and where a great deal of the excitement lies. Several efforts are under way – high throughput screens – to search rapidly for compounds that can upregulate the production of SMN protein by the SMN2 gene, and to improve the transcription of SMN protein by the SMN2 gene, thus improving yield. It is significant that compounds already identified by various screens include some that are already FDA approved.

The next step in this process is to identify the most promising of these compounds, seek ways to increase their effectiveness, and remove toxicity problems, if any. Then, these compounds can be tested in mouse models if necessary, or move directly into (human) clinical trials.

The stunning character of the SMA gene and the unique opportunity that it presents constitute the most dramatic opportunity for SMA research. But it is not the only opportunity.

Gene Therapy: Replace the Gene.

The “gene” referred to here is the “SMN1″ gene, the critical gene that is deleted in nearly all (97%) SMA patients. The goal here is to put a new SMN1 gene back in to the patient. This would see the development of a means of introducing DNA into the target tissue and permitting stable transcription and translation thereafter. The central issue is the identification of a vector construct (delivery system) which can both target motor neurons and mediate long term SMN expression therein.

Protein Therapy: Inject the missing protein

This requires identification of a protein domain which if expressed on a viral surface or fused to SMN protein or even DNA encoding SMN would, following systemic, intrathecal, or intramuscular administration, mediate viral or fusion molecule uptake into the motor neurons.

This approach may see configuration of an SMN encoding genetic construct which if placed in a stem cell would permit the secretion of the SMN protein or an SMN fusion protein.

Bring in a Sub: Find a drug that can do the job of the missing protein.

Proteins are large, complex molecules. Thus, the experience with identifying small molecules which can functionally replace proteins has not been encouraging. However, proteins are also multifunctional molecules which over the millennia have acquired (and lost) actions often impacting the same or closely related biological processes. It may be that one of these functions is in particular pathogenic, the replacement of which would have therapeutic benefit, somewhat simplifying the small molecule approach.

The 294-amino acid SMN protein is involved in RNA metabolism, specifically the assembly of the precursor messenger RNA (pre-mRNA) splicing apparatus (the spliceosome), participation in the process of splicing itself, as well as transcriptional activation. In this case, it would mean the identification of a small molecule which can do the work of the SMN protein.

Treat the Symptoms, not the Root Genetic Cause.

Here, the task is to identify interventions which moderate the disease process, but are not specific to the underlying genetic defect.

The goal here is the identification of drugs which modulate the progress of the disorder, for example, those conferring cytoprotection to the target tissues, resulting in an attenuation in the cellular loss of function and death caused by the underlying genetic defect. In general, these may be trophic, anti-apoptotic, antioxidant or a member of some other class of myo/neuroprotective compounds.

In SMA specifically, these may be agents which render motor neurons less susceptible to the toxic effects of SMN depletion, or possibly enhance the ability of motor neurons to sprout extra connections to muscle fibers and/or maintain those connections once made to increase the strength of the muscles that they innervate.

Stem Cells: Grow new motor neurons.

Potential stem cell therapies may see the configuration of stem cells secreting SMN.

Animal Models

There is rapid progress in the six areas outlined above. Concurrently, has been the successful development of genetically and clinically faithful mouse models of SMA.

Human tests are costly both in terms of time and resources. A critical “proof of principle” is afforded by mouse models genetically engineered to have the human disease. The murine (mouse) SMN null/human SMN2 transgenic mice are genetically faithful models of SMA, developing an SMA phenotype (physical characteristics). With such models, one is now in a position to test the various therapeutic agents both alone and in combination, looking for possible synergism of action. The mice will be useful in Track Five outlined above.

Clinical Trials

Ultimately, clinical trials will be designed to assess a therapy’s effectiveness. Such studies are generally difficult and expensive to organize. The demonstration of a “wonder drug” with a very dramatic therapeutic effect on SMA would be relatively easy since a trial showing such an effect would not need a large number of study entrants. However, in the absence of such an effective drug, it becomes more difficult to demonstrate unquestionably that a given treatment will produce small improvements; requiring in a perfect world, a randomized prospective trial employing placebo in half the study entrants. As desirable as this might be, empirically it often does not occur; parents of children with fatal disorders are, unsurprisingly, unwilling to allow them a 50% possibility of receiving no treatment.

Thus, the next best alternative is establishing the clearest possible natural history of the disease in an untreated genetically and clinically well defined group prior, then comparing this natural history to that of a similar or identical group which has undergone the treatment in question.

There is animated discussion about a number of compounds with potential for SMA. High throughput screens by various research teams have resulted in leads on possible compounds that may:

  • Upregulate production of SMN protein by the SMN2 gene;
  • Improve transcription of SMN protein by the SMN2 gene, thus improving “yield”.

Compounds identified by the various screens include some that are already FDA approved. Clinical trial of one or more of these compounds may be initiated soon.

Translational Research: New excitement about SMA.

Translational research is focused, goal-oriented and milestone-directed research associated with the “translation” of basic science discoveries to clinical treatments.

Unlike traditional investigator initiated grant funding, translational research is intended to be focused and rapid. It is intended to be applied to diseases for which late-stage therapeutics development is appropriate. These are cases in which the cause is known, there is sufficient understanding of the disease mechanism, and there is apparent feasibility for identifying treatments based on that mechanism.

Spinal muscular atrophy meets those criteria. In fact, this excerpt from the minutes of a February 2002 meeting of the Advisory Council of the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) explains the excitement:

“Spinal muscular atrophy was chosen because of the severity of the disease, its relatively high incidence, and the fact that the gene has been identified and the gene product is known, resulting in leads on possible treatments. There is a gap in funding to advance research on SMA, but if progress can be made, it would have implications for other diseases.”

There is tremendous – unprecedented – potential for a treatment for SMA. But there is a major gap in SMA research funding.

That gap must be closed.