Spinal Muscular Atrophy
In the last few years, the use of relatively small molecules such as oligonucleotides to alter the transcription of mutated RNA to produce a functioning protein has been developed. Because they are small molecules, they can be delivered with relative ease to the desired site. This technology has been applied to the treatment of spinal muscular atrophy (SMA) with considerable success.
Survival motor neuron gene product is essential for the health of the anterior horn cells of the spinal cord of the central nervous system. In the human genome there are two copies of the survival motor neuron gene, labeled SMN1 and SMN2. SMN1 normally produces a functional protein that is stable and necessary for the anterior horn survival. All patients with SMA have mutations in SMN1 that result in the gene being inactive. The protein product of SMN2 is usually truncated and not very stable, though it has some function. The severity of the resulting disease is influenced by the number of copies of the SMN2 gene present, and thus the available amount of partially functional SMN2 product. The oligonucleotide, in this case delivered via lumbar puncture, serves to alter the splicing of the protein product from SMN2, allowing the production of the more effective and stable protein with properties more similar to the SMN1 protein, thus ameliorating the effect of the SMN1 mutation. The patient, however, requires the administration of the therapeutic oligonucleotide indefinitely.
Gene Editing
The Gold Ring of therapeutic intervention, being able to actually correct the gene defect in any given disease, is still a goal of medical science. For the first time, this is a realistic aspiration due to the identification, development, and application of the gene editing tool Cas9 and CRISPR-Cas9 techniques.2 This new technology allows the production of a custom piece of DNA (cassette) that can repair the defective gene if incorporated into the DNA sequence of the host. The techniques necessary to introduce the therapeutic cassette to the affected cell and encourage the incorporation of the new material into the DNA have largely been developed already. The hurdle has always been the difficulty producing the therapeutic cassette for the given defect. The application of the CRISPR-Cas9 technology offers the promise of being able to produce a custom cassette specific for the given mutation, and thus potentially correcting the mutation involved in a wide variety of diseases.
The last quarter century has seen the expansion of the genetic techniques to allow the recognition and diagnosis of diseases that had resisted definitive diagnosis up to this time. These techniques have also led to the uncovering of disease mechanisms previously opaque to our understanding. The next quarter century promises to produce an explosion of therapeutic possibilities on a scale previously unimaginable. Despite the considerable initial expense of these new therapies, I believe they will be of incalculable value going forward.
References
1. de Koning AP, Gu W, Castoe TA, et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.
2. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.