SMA Research


An Informed and Focused Strategy

FightSMA works closely 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, coordinating the efforts of numerous laboratories making the most effective use possible of precious financial resources.
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 resources they can muster. It is a worthy and noble fight. And 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 starting with the 1995 discovery of the gene that is responsible for SMA.
In SMA, the “survival motor neuron,” (“SMN1″), gene located on Chromosome 5 is deleted . The SMN1 gene makes the vital SMN protein which, as the name suggests, is necessary for the survival of motor neuron cells that interface with our muscles. In the absence of the SMN1 gene and associated reduction of SMN protein, the motor neurons die off and the muscles that depend on the motor neurons waste away or atrophy. In the most severe type of SMA, infants generally do not survive to their second birthday. In other milder cases, the disease can still be disabling and frequently life-shortening. The tremendous potential for treatment lies in the unusual nature of the SMN genetics. 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 for SMN .
5. Administer protective or growth-enhancing agents.
6. Stem cell therapy.
1. Upregulation: Trick the Gene

The “gene” referred to here is the “SMN2″ gene. This is the “spare tire” gene that is still found in the genome of all children with SMA, 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 motor neuron survival and hence muscle strength. SMN protein has been found to play a critical role in RNA splicing and transport in motor neurons; it is these roles that are felt to be critical to motor neuron health and survival.

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; the number of SMN2 genes is higher in mild cases of SMA than in infants with severe SMA. The induction of SMN2 to increase the amount of SMN protein that is made 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. Ongoing research studies have provided leads on compounds which may increase the influence of this second copy of SMN (“SMN2″).

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

2. 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. There has been recently exciting work using adenovirus associated virus (AAV) SMN therapy in mouse models.

3. 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.
4. 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.

5. 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 motor neurons, 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.

6. Stem Cells

Animal Models
There is rapid progress in several of the six areas outlined above. The human testing that constitute the next important phase is costly both in terms of time and resources. Fortunately there has been the successful development of genetically and clinically faithful mouse models of SMA. The murine (mouse) SMN null/human SMN2 transgenic mice are genetically faithful models of SMA, developing an SMA phenotype (physical characteristics).

Thus a critical “proof of principle” can be afforded by mouse models genetically engineered to have the human disease. 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 particularly useful in Tracks one, two and 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 trialing 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, one 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. Finally the identification of a presymptomatic SMA children such as those identified by newborn screens will allow treatment before motor neuron loss. 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.

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