Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by muscle atrophy and weakness due to degeneration of the anterior horn cells in the spinal cord. A great need exists for an effective treatment of SMA, a disease that often causes severe disability in patients who are cognitively intact and can have a normal life expectancy. Unlike many other neurologic diseases, SMA can be easily diagnosed through genetic testing. Also, preclinical progress over the last 2 decades has been major, with the discovery of the gene and of a “druggable” modifying gene that provides one of several promising targets for treatment. SMA is rare but is a common orphan disease, so trials should be feasible, raising the hope that we will find effective treatments for this disorder.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by muscle atrophy and weakness due to degeneration of the anterior horn cells in the spinal cord. Hoffmann and Werdnig first independently described this disorder in the 1890s, and the genetic defect was localized to 5q11.2-13.3 a century later. The discovery of the underlying mutation in the Survival of Motor Neurons 1 (SMN 1) gene has accelerated preclinical research leading to treatment targets and transgenic mouse models, but there is still no effective treatment. The clinical severity is inversely related to the copy number of SMN 2, a modifying gene producing some full-length SMN transcript. Drugs shown to increase SMN 2 function in vitro , therefore, have the potential to benefit SMA patients .
As several drugs are approaching clinical investigation, the following elements become important as a basis for successful clinical trials. First, we need recent data on the natural history of SMA. Second, we need sensitive, reliable and clinically meaningful outcome measures. Third, we need an SMA clinical trials infrastructure that allows for adequate patient recruitment and that makes it easy for patients to participate in trials.
Historically, three types are defined clinically but they overlap, so that the classification is often not used in clinical research . SMA 1 is designated as that of patients who have onset before 6 months of age who never achieve the ability to sit. SMA 2 is defined by onset between 6 and 18 months and not reaching the motor milestone of standing. Patients who have SMA 3 by definition have disease onset after 18 months and gain the ability to walk. In addition, the term SMA 4 is sometimes used to describe patients who have adult-onset SMA and achieve the ability to walk. Children who have SMA 2 typically survive to adulthood. SMA 3 patients have a normal life expectancy.
The natural history of SMA, especially for the more severe phenotypes, is a moving target, as illustrated by several studies conducted in recent decades. Byers and Banker described 25 SMA 1 subjects in 1961 with a mean age at death (n = 23) of 10 months (range 17 days to 52 months), and a mean age of 17 months (range 10–24 months) in those who survived (n = 2). Zerres and Rudnik-Scho¨neborn reported outcomes in 197 SMA 1 subjects in 1995 and found a survival probability of 32% at 2 years, 18% at 4 years, 8% at 10 years, and 0% at 20 years. Borkowska studied SMA 1 patients who survived past 36 months, and found a mean age at death (n = 18) of 11 years (range 5–24 years). In a recent, United States registry-based study of 150 patients who had SMA 1, among patients born between 1980 and1994, 57 (80.3%) had died with a mean age at death of 17.9 months (range 1.0–193.5) compared to 28 (35.4%) had died with a mean age at death of 22.1 months (range 2.5–112) among those born between 1995 and 2006 .
The natural history of SMA 2 and 3 suggests that patients enter a chronic phase with little if any disease progression. Although a cross-sectional study found better performance on timed tasks in younger, compared with older, ambulatory patients who had SMA , longitudinal studies suggest that motor function often does not change over time periods that can be readily studied in clinical trials. Over periods of several years, loss of motor function is frequently observed . However, in a prospective study, improved motor function and acquired milestones were documented . The Dallas-Cincinnati-Newington Spinal Muscular Atrophy (DCN-SMA) study group found no change in muscle strength over 8 years in a cohort of patients with SMA 2 or 3. No mortality occurred during the study .
Outcome measures
Quantitative muscle testing (QMT) using the Richmond Quantitative Measurement System was used to test grip, knee flexion and extension, and elbow flexion in 12 children aged 2 to 14 who had SMA. QMT showed greater variability among the weakest children than did other measures. The investigators therefore concluded that a motor function measure may be more useful in clinical trials of childhood SMA than QMT . Myometry using a hand-held dynamometer may be less fatiguing than QMT, and it does not require expensive and fixed equipment. Three muscle groups, elbow flexors, knee flexors, and knee extensors, have been reported as showing the feasibility and reproducibility of QMT when tested with a hand-held device in 33 SMA patients . Reference values for maximum isometric muscle force in hand-held dynamometry have been established in 270 children aged 4 to 17 . In addition to issues related to cooperation and variability in children, motor function measures are often considered more inherently clinically meaningful than muscle strength measures.
Several gross motor function measures have been investigated in SMA. The gross motor function measure (GMFM), a proprietary instrument (McMaster University) has been validated in children who have SMA and has shown high interrater reliability. The GMFM contains 88 items in five dimensions: (1) lying and rolling, (2) sitting, (3) crawling, (4) standing, and (5) walking. Patients continue in each dimension to their maximum ability. The American Spinal Muscular Atrophy Randomized Trials (AmSMART) investigators found the GMFM reliable in children older than age 2 and all subjects performed in at least two dimensions . An alternative scale, the Hammersmith Functional Motor Scale (HFMS), has been developed specifically for SMA 2 and takes less time to administer than the GMFM . However, the HFMS is specific to non-ambulatory SMA patients so that its use in clinical trials can be limited by a floor or ceiling effect. Recently, an expanded HFMS has been proposed to broaden the range of motor function tested in the original HFMS .
Timed tasks, such as time walking, can be considered as outcomes in ambulatory subjects, because they are easily quantifiable, meaningful to patients, and have been successfully used in neuromuscular research .
Pulmonary function measures can be performed in patients aged 5 or older. Potential measures include inspiratory vital capacity, forced expiratory vital capacity (as a percent predicted for age and height) , maximal inspiratory and expiratory pressures, and peak expiratory flow . Pulmonary measures have been validated in SMA clinical research .
Quality of life can be evaluated in subjects aged 2 to 18 years using the PedsQL Generic Quality of Life Inventory instrument , which has been validated by the AmSMART investigators for SMA . The development and validation of a neuromuscular module are in progress. In subjects 18 years and older a range of quality of life measures are available, including the 36-Item Short Form Health Survey; it is a generic measure of health-related quality of life designed for self administration that can be completed in less than 30 minutes by most patients . Controlled clinical trials are required by the United States Food and Drug Administration (USFDA) to approve drugs for the treatment of patients. Therefore, clinical trials are associated not only with potential scientific benefit to the community, but also potential benefit to the population of SMA patients. In addition, some patients perceive direct benefit from trial participation, for example in terms of learning more about their disease or in terms of frequent interactions with healthcare professionals . However, recruitment has been difficult in recent US clinical trials for SMA .
Drug trials published
Albuterol
Albuterol is thought to have an anabolic effect on muscle, but more recently has also been suggested as an up-regulator of SMN 2 function. An open-label study of albuterol over 6 months in 13 patients with SMA 2 or 3 showed modest benefits in strength .
Gabapentin
Two placebo-controlled trials of gabapentin in SMA were negative . The initial trial included 84 adult patients with SMA 2 or 3 who were treated over 12 months and evaluated with myometry. A second trial included 120 patients with SMA 2 or 3, aged 5 to 60, who were also treated for 12 months and evaluated with myometry.
Riluzole
Riluzole, a neuroprotective agent with modest benefit in amyotrophic lateral sclerosis, showed possible benefit in seven patients who had SMA 1 compared with three placebo-treated patients, with a targeted follow-up period of 9 months. A subsequent open-label study had insufficient enrollment but pharmacokinetic studies in three subjects showed adequate blood levels after oral administration to infants .
Phenylbutyrate
Phenylbutyrate showed promise in an open-label pilot study of 10 patients who had SMA 2 treated for 9 weeks , but a placebo-controlled trial of intermittent treatment over 13 weeks in 107 SMA 2 patients aged 2 to 13 was negative . Both phenylbutyrate studies were designed to demonstrate functional motor benefit.
Valproic acid
Valproic acid resulted in increased SMN mRNA, and protein levels increased after treatment in 7 of 10 carriers and 7 of 20 patients but remained unchanged or decreased in 13 patients . In a second open-label pilot study in the United States, 7 patients aged 17 to 45 who had SMA 3 or 4 treated with valproic acid for 8 months on average showed improvement in muscle strength and function .
Hydroxyurea
Hydroxyurea treatment for 8 weeks in 33 patients with SMA 2 or 3 has shown slight benefit in muscle strength scores . This trial was not placebo-controlled.
Drug trials published
Albuterol
Albuterol is thought to have an anabolic effect on muscle, but more recently has also been suggested as an up-regulator of SMN 2 function. An open-label study of albuterol over 6 months in 13 patients with SMA 2 or 3 showed modest benefits in strength .
Gabapentin
Two placebo-controlled trials of gabapentin in SMA were negative . The initial trial included 84 adult patients with SMA 2 or 3 who were treated over 12 months and evaluated with myometry. A second trial included 120 patients with SMA 2 or 3, aged 5 to 60, who were also treated for 12 months and evaluated with myometry.
Riluzole
Riluzole, a neuroprotective agent with modest benefit in amyotrophic lateral sclerosis, showed possible benefit in seven patients who had SMA 1 compared with three placebo-treated patients, with a targeted follow-up period of 9 months. A subsequent open-label study had insufficient enrollment but pharmacokinetic studies in three subjects showed adequate blood levels after oral administration to infants .
Phenylbutyrate
Phenylbutyrate showed promise in an open-label pilot study of 10 patients who had SMA 2 treated for 9 weeks , but a placebo-controlled trial of intermittent treatment over 13 weeks in 107 SMA 2 patients aged 2 to 13 was negative . Both phenylbutyrate studies were designed to demonstrate functional motor benefit.
Valproic acid
Valproic acid resulted in increased SMN mRNA, and protein levels increased after treatment in 7 of 10 carriers and 7 of 20 patients but remained unchanged or decreased in 13 patients . In a second open-label pilot study in the United States, 7 patients aged 17 to 45 who had SMA 3 or 4 treated with valproic acid for 8 months on average showed improvement in muscle strength and function .
Hydroxyurea
Hydroxyurea treatment for 8 weeks in 33 patients with SMA 2 or 3 has shown slight benefit in muscle strength scores . This trial was not placebo-controlled.
Related posts:
Glial Cells in ALS: The Missing Link?
Androgen Receptor Function in Motor Neuron Survival and Degeneration
Motor Unit Number Estimation in the Assessment of Performance and Function in Motor Neuron Disease
The Role of Exercise in Amyotrophic Lateral Sclerosis
Respiratory Treatment of Amyotrophic Lateral Sclerosis
Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
