Newborn screening and gene therapy in SMA: Challenges related to vaccinations

Abstract

Spinal muscular atrophy (SMA) affects one in 7,500–10,000 newborns. Before the era of disease-modifying therapies, it used to be the major genetic cause of mortality in infants. Currently, there are three therapies approved for SMA, including two molecules modifying the splicing of the SMN2 gene and one gene therapy providing a healthy copy of the SMN gene with a viral vector. The best effects of any of these therapies are achieved when the treatment is administered in the presymptomatic stage of the disease, therefore newborn screening programs are being introduced in many countries. Patients identified in newborn screening might be eligible for gene therapy. However, gene therapy and the associated administration of steroids in newborns might interfere with the vaccination schedule, which includes live immunization against tuberculosis in some countries. The timing of gene therapy in patients who received live vaccinations has not yet been addressed neither in the clinical trials nor in the existing international guidelines. The Polish Vaccinology Association has developed the first recommendations for gene therapy administration in newborns who received live vaccination against tuberculosis. Their statement was implemented in the current guidelines for Polish SMA patients identified in the newborn screening program and might be helpful for medical professionals in other countries where live vaccine against tuberculosis is still in routine use in newborns.

Early Development of Spinal Deformities in Children Severely Affected with Spinal Muscular Atrophy after Gene Therapy with Onasemnogene Abeparvovec—Preliminary Results

“…This is in line with the observation that early treatment will lessen the severity of the disease. Previous studies have stated that the pharmaceutical treatments for SMA are most effective if administered immediately after or even before the onset of clinical symptoms [ 14 , 36 ]. Therefore, a newborn screening has been proposed to be the most effective way to ensure early diagnosis [ 37 ].…”

“…Kotulska et al speculated about the same issue in their review on SMA. Although overall motor development and survival of the pharmaceutically treated SMA patients improved, the patients still developed early-onset scoliosis [ 14 ]. In this study, the amount of fewer gene copies showed a statistical significant correlation with higher kyphotic curve angles.…”

“…Immediate administration-related adverse effects of onasemnogene abeparvovec include pyrexia and vomiting [ 43 ], acute liver failure [ 44 ], transient thrombocytopenia, and elevated troponin levels [ 14 , 45 ]. Additionally, fatal thrombotic microangiopathy has been described [ 46 ].…”

“…Nonetheless severe scoliosis may occur in patients with SMA types 1 and 2 at a young age [ 8 , 10 ]. Previous literature states that the novel drug therapies have shifted the focus of scoliosis incidence from SMA type 2 patients more towards to SMA type 1 children [ 13 , 14 ].…”

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

“…A discussion of the disease and some of the diagnostic issues was published in 2020 and provides information that is potentially useful as screening policies are developed [950]. The Polish Vaccinology Association published the first recommendations for gene therapy for newborns who received live vaccination against tuberculosis, which might be helpful in other countries where live vaccine against tuberculosis is still used [951].…”