Saturday, July 22, 2017

The future of SMA therapy

Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Jul 23. doi: 10.1038/gt.2017.52. [Epub ahead of print]

Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene provides, for the first time, a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases.

From the article


The children treated in the recent nusinersen trial showed acceptable tolerance to the intrathecal procedure and the vast majority of serious adverse events reported were disease related. However, it is important to note that these children showed progress but did not achieve completely normal motor function in the timescale reported in the trial, and face an uncertain future as they grow and develop from a baseline of established neuromuscular weakness. Therefore, despite the promise provided by nusinersen, it should be seen as the first step in a transformative environment for SMA therapy. There is still much progress to be made and a number of other approaches are under investigation, including modified ASOs to increase cell penetration, oral small molecule approaches aimed at increasing SMN levels, and virally delivered gene replacement therapy (a list of ongoing clinical trials in SMA is available at It will be difficult to recruit any drug naïve patients in which these agents can be tried, making it challenging to identify the clinical effectiveness of newer agents, except perhaps as adjunctive therapy. Clinical trial methodology in SMA will have to accommodate this complexity, as it will not be ethically acceptable to prevent subjects in new trials taking an established therapy, if available. Trials and protocols of combinatorial therapies aiming for synergies and complementation are envisaged. It remains possible that SMN restoration might not be a sufficient therapy for all patients with SMA, either because it functions in a time-dependent window in early development and will never prevent the slow progressive decline seen in older children and adults, or because the typical insidious clinical presentation of milder forms of SMA does not allow early treatment in the absence of post-natal screening. For these reasons, a whole range of other, non-SMN, pathways are under investigation, including those based on modifiers of the pathobiology and phenotype. The future of SMA therapy covering the whole period from infancy to late life may well require a range of therapies in combination. Even if SMA can be treated pre-clinically, it is well established that in the most severely affected children, the pathological process begins in utero.15Even with the best approaches to SMN replacement, there may be late effects in neuromuscular weakness due to a reduced functional reserve.


  1. I was informed of a situation where a 5 weeks old infant was diagnosed with SMA. At 8 months of age on therapy with nusinersen he is thriving. His parents recently conveyed that they now want to withdraw his therapy, since they do not want to live with the burden of a handicapped child or, perhaps, they do not want their child to have the burden of being handicapped.

  2. December 23, 2016 was a big day for my family and me. Not only did my sister go into labor with she and her husband’s first child on this day, but it also was the day it was announced that the first FDA-approved treatment for spinal muscular atrophy was made available to the public. Since then, this treatment, called Spinraza, has been a prime point of discussion within the SMA community.

    Some of you may be baffled by the title of this column. You may be thinking, “Why in the world would someone who has a severe neuromuscular disease not jump at the chance for some sort of treatment?” I understand the confusion some of you may feel toward this notion, but it’s important to look at this from a multifaceted perspective. Furthermore, people need to realize that not every person who has SMA is the same. Each of us possess a unique set of personalities, goals, desires and perspectives.

    For the past few months, I’ve had multiple conversations with other SMA adults regarding Spinraza. Some were elated by the news back in December, and have either started to undergo treatments or are working on getting it approved by their insurance providers. Others, however, are either skeptical about Spinraza, or simply are uninterested in seeking the treatment for a variety of reasons. While all of us are overjoyed by how many kids and newly diagnosed patients already have received Spinraza and have yielded tremendous results, those of us who are SMA “veterans” have many things to consider before going through the treatment process.

    Having lived with SMA my entire life, I can tell you that I have a complicated relationship with my disease. When I was first diagnosed at 18 months, it was a nightmare for my parents. Not only did the doctors tell them I would never walk and that my muscles would decay over time, but they also were told I had a maximum life expectancy of 18 years. This is typically how most SMA stories begin, and it would cause any parent to shutter.(continued)

  3. (continued)Over time though, the possibility of a “normal” life became a reality for myself and many others. I went to school, made plenty of friends, got involved in different things and drove my parents crazy as a teenager. Now, as a 23 year-old college graduate working on a writing career, that initial stage of terror and hopelessness my parents experienced when I was first diagnosed seems more like a faint memory. I know how to handle SMA on a daily basis, and there are very few obstacles I face that come as a surprise or that I don’t know how to deal with.

    It’s because of this that many SMA adults have a bittersweet reaction to the notion of a treatment. On the one hand it’s a blessing for younger and future generations of SMA patients and their families. Most families I’ve talked to who have young or newly diagnosed patients have been able to get their children the Spinraza treatment without any insurance battles, or other bureaucratic obstacles. On the adult side of the spectrum, many of us (including myself) have been denied by our insurance providers on the basis that we’re too old to receive the treatment. Others SMA patients simply don’t want to go through it at all, as it is a matter of both time and cost that would interfere with their work and personal lives.

    I fall somewhere in between wanting Spinraza and not wanting to pursue it at the moment. While I’ve been denied by insurance, I’m also OK waiting a little longer to receive it or some other treatment down the road. Right now I’m more focused on my career, getting a new wheelchair and hiring more caregivers for the future. As I mentioned earlier, receiving Spinraza is a costly and time-consuming process, which for some SMA adults is just as burdensome and draining as the actual disease.

    I’m in no way trying to say that SMA isn’t as brutal and frustrating for adults as it is for those who are newly diagnosed. There are days when it takes a toll on me physically, emotionally and mentally. There are days when all I wish for is the ability to raise my arms on my own and hold someone who I care about. Just because I’ve lived with this disease my whole life and know how it works, doesn’t make living with it any easier.

    All I’m saying is that the introduction of a treatment is more complicated than most people realize. I am certainly glad that Spinraza exists, and that we’ve already seen incredibly positive results from it across the SMA community. Yet, at the same time, I want people to understand that it’s OK for people who have SMA not to want the treatment.

    We all may share the same neuromuscular condition, but it doesn’t define who we are. We’re still individuals and, treatment or no treatment, our decisions are our own.