Polio was once among the most feared diseases in the world. This fear, as is usually the case, is driven by the fact that many people have so little information about it, except that it can lead to a collapse in independent mobility and potentially death.
To help patients with severe polio breathe, patients were confined into what was known as an “iron lung,” a device that essentially keeps the patient alive by doing the breathing for them. While it undoubtedly extended survival, it also condemned a previously healthy individual to a lifetime spent in this contraption.
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With the dawn of polio vaccines, this disease has largely (but not completely) disappeared off the face of the earth. However, this chapter on medicine and human history provides us with a glimpse into the natural anxieties surrounding diseases that can cause the loss of ambulation and independent living. And for many of these diseases, such as spinal muscular atrophy (SMA), there are no vaccines that can protect one from developing this disorder.
Of course, this is because SMA is a genetic condition, not an infectious one. The good news about genetic disorders is that they can generally be picked up on when a patient is still in his infancy, allowing appropriate treatment regimens to be initiated. The bad news is that we are currently behind in offering gene therapy that will truly make a curative difference.
While current SMA therapeutics can offer symptomatic improvement, they are not effective in halting disease progression indefinitely. There is often a point upon which the disease becomes lethal and palliative care becomes necessary.
In this article, we will take a look at some of the more promising treatments available for SMA and look ahead at some advanced therapeutics that are under investigation.
Assessing the Merits of Current SMA Therapies
Approximately 30 years ago, scientists have yet to identify a clear molecular target for the purpose of developing SMA therapeutics. Hence, clinical trials were few and far between.
However, the discovery of the SMN gene largely kickstarted efforts to tackle this disease. Many studies began to be conducted on mice with 2 copies of the human SMN2 on a null smn-/- background, which mimics the clinical conditions of a severe SMA phenotype.
One of the first waves of drugs that were used to treat SMA compounds aimed to increase SMN levels in both in vitro studies and studies involving animal models. Nevertheless, trials involving several promising agents, such as valproic acid and hydroxyurea, did not demonstrate any tangible clinical benefits.
“However, there are now many new small molecules that have been discovered and developed specifically for their ability to affect the splicing of the SMN2 gene to increase the amount of full-length SMN mRNA transcript,” Kolb and Kissel wrote in Neurologic Clinics.
Another group of drugs that has become the mainstay treatment for SMA are antisense oligonucleotides, among which is the highly lauded drug nusinersen. Antisense oligonucleotides essentially work by enhancing RNA structure, stability, and function. Nusinersen was first approved by the United States Food and Drug Administration in 2016, and its use in SMA is supported by an abundance of clinical trials. Studies have found that it can greatly elevate SMN protein levels in the cerebrospinal fluid and help patients increase their walking distances. There are reports that infants with a shorter disease duration are more likely to benefit from this drug compared to those with a longer disease duration.
The main downside to antisense oligonucleotides like nusinersen is that its ability to restore SMN levels are confined to the central nervous system; studies have suggested that the restoration of SMN may also hold significant clinical value in peripheral tissues and organs.
Gene Therapy: The Elusive Holy Grail
Most papers today discussing the future of drug development mention gene therapy, a topic that is often dissected and debated, often with a whiff of longing. This is because gene therapy is the perfect encapsulation of the old saying “already but not yet”—many of the infrastructures for gene therapy are already available, yet its full powers have not yet been harnessed.
The same is true for gene therapy in SMA. Because we know the genetic defects driving the disease, gene therapy can theoretically correct those defects and “cure” the disease for all intents and purposes. This has been successfully conducted in mouse models with severe SMA.
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There are important questions to consider before gene therapy can be fully implemented in SMA: is there an optimal time period during which gene therapy can alleviate symptoms for good? Do effects wear off? Does gene therapy offer a complete curative solution, or are any effects simply temporary? How long is the expected time period between gene therapy and the full resolution of symptoms, if that is indeed achievable?
These questions are not unique to SMA; they are also actively discussed in other neurodegenerative disorders, such as muscular dystrophies, Alzheimer disease, Parkinson disease, and amyloid lateral sclerosis, among others. The way we get answers on the viability of gene therapy is the way the scientific community has always gotten answers—through trial and error, success and failures, and an iron-willed persistence to do right by our patients.
References
Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. Published online November 1, 2016. doi:10.1016/j.ncl.2015.07.004
Jablonka S, Hennlein L, Sendtner M. Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders. Neurol Res Pract. Published online January 4, 2022. doi:10.1186/s42466-021-00162-9
