Spinal Muscular Atrophy (SMA) is the leading heritable causes of infant mortality worldwide. It is a neurodegenerative disorder that presents as progressive muscle wasting and loss of motor function. As motor nerves are located in the spinal cord, a vast decrease in muscle control for several activities (such as breathing, walking, head and neck control, swallowing) occurs. SMA is an autosomal recessive disorder caused by deletion of the survival motor neuron gene 1 (SMN1).
There are four types of SMA: Types I-IV. Children with type I SMA never sit and life expectancy is short; children with type II SMA never walk independently; however, children with types III and IV SMA achieve independent ambulation. They are able to walk without assistance, at least for some time in their lives. Drugs that improve motor function and life expectancy are needed.
- 1 in 6,000 births is an SMA baby
- 1 in 40 adults is a carrier of the gene mutation that causes SMA
- The child of 2 carriers has a 1-in-4 chance of having SMA
- 7.5 million Americans are carriers
- There is no FDA-approved drug for SMA and the pipeline is very small (e.g., ISIS/Biogen antisense drug in phase IIa)
Historically only 1-in-10 drugs in phase II reaches the market; We need to fill the pipeline
Currently, there is no pharmacologic treatment for SMA. None of the compounds that reached clinical trials has elicited a convincing improvement in muscle function or survival in patients. New therapeutic modalities for treatment of SMA being actively pursued include: antisense oligonucleotides therapies; gene transfer using viral vectors; and motor neuron differentiated stem cells. SMN1 gene replacement has shown promising results in animal models and is entering human clinical trial stage. Stem cell based motor neuron replacement has IND approval, but it has been on clinical hold since 2010. The DcpS inhibitor, RG3039, has completed phase Ia clinical trials with no adverse effects; however, no further development has been reported with this compound, and there is a clear need for additional drug candidates.
SMA was mapped to chromosome 5q13. This region contains a 500 kb inverted repeat and is a hotspot for chromosomal rearrangement. Within this locus are two nearly identical SMN genes, telomeric SMN1 and centromeric SMN2, which encode the same protein: SMN. SMA carriers with one copy of SMN1 are clinically asymptomatic. The SMN2 mRNA undergoes alternative splicing, such that the majority of its transcripts skip exon 7, and produces a truncated, unstable SMN protein. The disease occurs when both copies of SMN1 are deleted, disrupted, or converted to SMN2 by homologous recombination. If SMN2 can be stimulated to express more full length SMN mRNAs, synthesis would be directed towards increased amounts of the active SMN protein. Although the level of SMN needed to maintain motor neurons is not known, doubling or tripling the amount of full length SMN2 mRNA should be clinically significant. A small molecule that safely increases cellular levels of the SMN protein from the SMN2 gene could dramatically improve the quality of life for individuals with SMA.
In collaboration with Prof. Elliot Androphy at Indiana University, we are actively developing novel therapeutics for SMA. Initially, we identified compounds with a functional, cell based assay, which was target agnostic, and which identified compounds that increased SMN2 protein, either by increasing transcription of SMN2 or increasing the stability of SMN2 protein. Following medicinal chemistry optimization at the LDDN, we developed novel series that validate this approach, and we now have lead compounds that show very promising pharmacokinetics and efficacy in mouse models of SMA.