As the feasibility of phase 1 clinical trials for prenatal spinal muscular atrophy (SMA) therapies is explored, patient and parent input on prenatal testing and possibly treatment is a valuable tool for guiding research discussions.
Rapid diagnosis and treatment are crucial for infants affected by spinal muscular atrophy (SMA), and with the advent of genetic testing, neonatal and even prenatal diagnosis has become possible. Parent and patient perspectives are important as prenatal diagnosis and treatment become increasingly feasible, and a recent study published in Prenatal Diagnosis found that many parents and adult patients affected by SMA view fetal testing and therapies in a positive light.
SMA is a rare genetic neurodegenerative disorder caused by mutations of the survival motor neuron 1 (SMN1)gene that inhibit SMN protein production. This leads to varying degrees of muscle weakness and atrophy, with symptoms of the most severe form of SMA, type 0, manifesting before birth.
Patients with type 0 SMA typically do not survive longer than 1 month after birth. Infants with type 1 SMA, which affects approximately 50% of SMA patients overall, typically show signs prior to 6 months of age and do not survive longer than 2 years. Patients with SMA type 2 typically survive into adulthood but are never ambulatory; those with type 3 show symptoms after 18 months and may walk independently but eventually require a wheelchair; and those with type 4 SMA develop proximal weakness in adulthood but remain ambulatory.
In recent years, several therapy options that can improve survival, reduce the need for ventilation, and facilitate better motor function and milestones for patients with SMA have become available. But these treatments hinge on early initiation to inhibit irreversible motor neuron damage and deliver maximal benefits. Therefore, diagnosing the most severe forms at birth or even prior to birth could improve outcomes for patients.
“As the possibility of prenatal therapies emerges, it is also important to assess whether this population’s historical interest in previous novel approaches also portends an interest in prenatal clinical trials,” the authors wrote. “Gathering stakeholder views can help inform conversations with regulatory authorities regarding trials for fetal therapies, and importantly, provide direction for future trials in considering their primary beneficiaries’ priorities and needs.”
The study included 114 participants—46 parents and 68 patients—who filled out a questionnaire designed by a multidisciplinary team and distributed by Care SMA. Most of the respondents were affected by types 2 and 3 SMA, and only 2 parents had received a prenatal diagnosis for their children. The median age at diagnosis was 15 months for patients who were diagnosed after birth. Of the patients, 63.3% received the antisense oligonucleotide nusinersen, 28.3% received gene therapy with zolgensma, and 14.7% received risdiplam or branaplan small molecule therapy.
Of the respondents who were affected by type 0 or 1 SMA, 80% strongly supported fetal testing and diagnosis, compared with 71.4% of respondents affected by SMA type 2 or 3. The majority of patients with SMA type 0 or 1 (77%) felt that their diagnoses were delayed, and 85% of those affected by SMA type 2 or 3 felt there had been a delay in their diagnoses.
Overall, 55% of respondents indicated that they would likely enroll in a phase 1 clinical trial for fetal antisense oligonucleotide therapy. Older respondents and those who felt their diagnosis was delayed were more likely to want to enroll in trials. If fetal antisense oligonucleotide or small molecule treatment becomes an established therapy, 78.9% of respondents would be likely to choose this route. Those who felt their diagnosis was delayed were more likely to choose a fetal therapy once they are established. Where fetal gene therapy is concerned, 61.1% of respondents overall indicated that they would be interested in enrolling in a phase 1 trial.
The survey results suggest that many patients affected by SMA and their parents have a positive attitude toward prenatal testing for SMA, and many would be interested in phase 1 trials of fetal therapies for SMA. This was especially true for respondents affected by more severe phenotypes of SMA. Respondents were even more likely to be interested if the therapies in question become established courses of treatment.
As the feasibility of phase 1 clinical trials for prenatal SMA therapies is explored, patient and parent input on relevant hypothetical situations is a valuable tool for guiding discussions. This is the first stakeholder survey involving prenatal SMA testing and therapy to the authors’ knowledge, and the results provide insight into how those most affected by SMA view fetal testing and potential prenatal therapies for SMA. In the future, further research can help determine the social factors that play into patients’ views on prenatal testing, trials, and therapies.
Schwab ME, Shao S, Zhang L, et al. Investigating attitudes towards prenatal diagnosis and fetal therapy for spinal muscular atrophy (SMA). Prenat Diagn. Published online August 27, 2022. doi:10.1002/pd.6228