Small Molecules (modulation of the SMN2 'back-up' gene)
Modulation of the SMN2 ‘Back-up’ Gene
For our lower motor neurons to function and remain healthy, our cells need to produce the survival motor neuron (SMN) protein. The ability to do this is mainly controlled by the survival motor neuron 1 (SMN1) gene.
The SMN2 gene also contributes to the production of SMN protein, though it only makes approximately 10% of that produced by SMN1. For this reason, SMA is caused only by mutations in the SMN1 gene and not SMN2, and also why SMN2 is often called the SMN ‘back-up’ gene.
Anyone who has SMA has at least one copy of the SMN2 gene. Individuals can have multiple copies of SMN2, and, in general, it seems that those with more copies have a less severe form of SMA.
Most of the SMN protein made by SMN2 (about 90%) is missing an important piece called exon 7. The remaining 10% of the protein produced by SMN2 includes exon 7 and is the same as that made by SMN1. A number of treatment strategies that target SMN2 to make more functional SMN protein are being explored; they aim to do this in one of three main ways:
- Correct SMN2 splicing, allowing SMN2 to more efficiently produce functional SMN protein.
- Increase the protein production from SMN2 leading to more functional SMN protein.
- Stabilise the functional SMN protein made by SMN2 and therefore make it last longer.
Small molecules are chemicals or compounds that are capable of treating or even curing a disease. These potential drugs may be used to increase the amount of SMN protein made by SMN2.
A multi-step process is used to convert small molecules into drugs:
- Researchers screen hundreds of thousands of chemicals through a process called ‘high-throughput screening’ in their search for a chemical that that might work for SMA, i.e. one that increases SMN protein levels.
- Using medicinal chemistry, scientists then modify the chemical numerous times trying to optimise its structure to make a safe and useable drug.
- These ‘optimised candidate drugs’ are then tested in animal studies for their efficacy and safety before they are trialled on humans.
- Successful optimised candidate drugs are then redefined as an ‘Investigational New Drug’ (IND) and an application is submitted for it to be approved for human clinical trials.
A number of companies and academic laboratories have small molecule programmes that are attempting to identify and develop compounds that target the SMN2 gene.
For an up to date view of progress see:
Roche/PTC Therapeutics (Phase 1 trials)
Paratek (pre-clinical trials of tetracycline)
CALIBR (pre-clinical focusing on optimising chemical properties of small molecule enhancers of SMN protein, led by Peter G Schultz)
Rubin lab at Harvard University (pre-clinical focusing on small molecule drug screening in motor neurons, led by Dr Lee Rubin)
Androphy lab at Indiana University (pre-clinical)
Pfizer (Phase 1 trials of RG3039, a.k.a. Quinazoline)