Co-founder, vice chair and CSO of the Spinal Muscular Atrophy Research Team and Director of R&D at Bristol-Myers Squibb, Timothy P. Reilly, PhD, DABT discusses Spinal Muscular Atrophy and his optimism for growing orphan disease market.

Orphan diseases used to be a lonely place in drug development. But with recent analyses showing high profitability potential, support from disease advocacy organizations, and new therapeutic approaches, biopharmaceutical companies are beginning to embrace rare diseases, including Spinal Muscular Atrophy.

Orphan diseases affect relatively small numbers of people (qualified as <200,000 in the USA). Historically, biopharmaceutical companies have given them a rather low priority because of many factors, such as a lack of mechanistic knowledge, a focus on unmet medical needs that affect larger portions of the population, or a perceived inability to get a suitable return on investment.

In the 1980s, legislation like the US Orphan Drug Act began to incentivize research to treat rare diseases, which helped spur a focus on orphan disease. But what truly caused the increased attention was the tidal wave of genetic and molecular information following the elucidation of the human genome and scientists’ subsequent ability to understand the fundamental underpinnings of rare diseases.

Orphan drug development is the perfect example of targeted, personalized medicine and there is increasing awareness among biopharmaceutical companies looking to move beyond blockbuster drugs that the orphan disease market represents an untapped growth opportunity. Recent analyses also suggest greater profitability potential relative to non-orphan drugs1. Spinal Muscular Atrophy is an excellent example of this changing landscape.

The Story of Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is an autosomal recessive, degenerative, neuromuscular disease. It is characterized by a loss of motor neurons in the brain and spinal cord, which then leads to muscle weakness and wasting in the proximal limbs, trunk and neck. Although there is variability across the spectrum of SMA, the disease ultimately results in paralysis, respiratory distress and early death.

The disease is the leading genetic cause of infant death, affecting one out of every 6,000 births (note: carrier frequency for the recessive gene is an astonishing 1 out of every 37 people). Many pediatric neurologists have had the unenviable task of telling a parent that their child has SMA and informing them of a tragic and uncertain prognosis. I know because I am the father of an 8-year-old son with Type 2 (intermediate) SMA, which means that he was never able to stand or walk, requires day-to-day assistance and is likely to face increasing health issues as he ages. What I have come to learn following my son’s diagnosis, however, is that there is cause for optimism.

SMA is a monogenic disease caused by a deletion (95% of cases) or mutation of the survival motor neuron 1 (SMN1) gene. This results in SMN protein deficiency, which leads to mRNA splicing defects, motor neuron dysfunction and defective neuromuscular junctions. An evolutionary duplicate gene, SMN2, with a single nucleotide substitution, leads to exon 7 skipping and only 10% of functional SMN protein. Copy numbers of SMN2 and output of SMN protein in fact define disease onset and severity. That is, the more copies, the less severe one’s disease. This also means that SMA patients have a built-in therapeutic mechanism. If greater levels of functional protein could be elicited out of each copy of this genetic backup, disease modification is theoretically possible.

Optimism for potential treatments or a cure has also been driven by many large disease advocacy organizations, like Families of SMA, Fight SMA, SMA Foundation and the Muscular Dystrophy Association, all of whom have provided indispensible support to academic investigators and biotechnology companies. Grass-roots organizations like our own, fund innovative research ideas that may ultimately lead to a cure. Also, the National Institutes of Health designated SMA as the disease closest to treatment out of more than 600 neurological disorders, and President Obama recently signed into law legislation that will advance developments for SMA and other rare diseases.

Is SMA Therapy on the Horizon?

Many innovative drug discovery/development efforts are now well under way2,3.They range from the repurposing of drugs approved for other indications (e.g. valproic acid) to generalized neuroprotective approaches (e.g. Trophos’ olesxime in Phase 2 clinical studies) to SMA-specific therapeutic approaches. Some, such as stem cell therapy and gene therapy aimed at reconstituting a functional SMN1 gene, are still in preclinical development. More advanced approaches include those aimed at inducing greater SMN expression from the SMN2 gene (e.g. Repligen’s RG3039 molecule in Phase 1), or those that correct splicing defects to increase production of fully functional SMN protein (e.g. Isis’ anti-sense oligonucleotide [ASO] SMN-Rx in Phase 1). There is enormous excitement surrounding this latter approach since ASO administration in mouse models of SMA has dramatically increased median survival from 10-14 days to 100-200 or more days4,5. These therapeutic opportunities have also attracted the interest of bigger players like Biogen-Idec (now in collaboration with Isis on their ASO), Roche (now in collaboration with PTC Therapeutics) and Novartis.

Hope for Orphan Diseases and SMA

The most useful approach will reveal itself over time, but as a parent of a child with SMA and as a pharmaceutical scientist always interested in new drug therapies to treat these diseases my hope is that this particular orphan disease drug development opportunity becomes a windfall of success for everyone involved.


  1. Meekings KN, Williams CSM, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discovery Today. 2012 (July); 17 (13/14): 660-664.
  2. Van Meerbeke JP, Sumner CJ. Progress and promise: the current status of spinal muscular atrophy therapeutics. Discov Med. 2011 (Oct); 12(65): 291-305.
  3. Lorson MA, Lorson CL. SMN-inducing compounds for the treatment of spinal muscular atrophy. Future Med Chem. 2012 (Oct); 4(16): 2067-84.
  4. Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, Krainer AR. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature. 2011 (Oct 5); 478(7367): 123-6.
  5. Porensky PN, Mitrpant C, McGovern VL, Bevan AK, Foust KD, Kaspar BK, Wilton SD, Burghes AH. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet. 2012 (Apr 1); 21(7): 1625-38.