In utero therapy for spinal muscular atrophy: closer to clinical translation

Abstract

5q-Spinal muscular atrophy (SMA) has been a trailblazer in the development of advanced therapies for inherited diseases. SMA is an autosomal recessive disorder affecting mainly motor neurons in the anterior horn of the spinal cord and brainstem motor nucle but currently considered a systemic disease. Advances in understanding the genetics of SMA led to the development of disease-modifying therapies, either transferring a healthy version of SMN1, the causative gene absent or altered in SMA, or modulating SMN2, a highly homologous but less functional version of SMN1, present in all patients. After successful clinical trials, these approaches have resulted in three marketed therapies. Severe SMA, 'type I', is the most common type and is considered both a developmental arrest and neurodegenerative disorder. As pathology starts during fetal life in type I patients, a cure is unlikely even when treatment is started shortly after birth in the pre- or mildly symptomatic state. In utero fetal therapy offers the opportunity to mitigate further or possibly prevent manifestations of the disease. This review discusses clinical and developmental aspects of SMA, the advanced therapies approved (gene therapy, antisense oligonucleotide and small molecule compounds), and the rationale, options and challenges, including ethical and safety issues, to initiate in utero therapy. Looking beyond sporadic case reports of prenatal intervention, clinical trials of in utero SMA therapy can be envisaged and should be carefully designed and evaluated to move closer to clinical translation.

Keywords: in-utero therapy; fetus; gene therapy; human development; pre-symptomatic; spinal muscular atrophy.

Figure 1

Possible threshold for development of prenatal spinal muscular atrophy neuropathology and extraneuronal manifestations. The amount of SMN protein present in spinal muscular atrophy (SMA) correlates with SMN2 copy number, a key factor in disease severity. Generic SMN levels are presented in the figure in two ways in SMA: as straight lines for average levels over time, and as diamonds to account for person-to-person variation, which in some cases, mainly with two or three SMN2 copies, may overlap considerably. SMN requirements are highest in the third trimester of fetal development and approximately the first 3 months after birth, then reduce (see green curve, based on Pérez-García et al. and Ramos et al.) Manifestations in individuals with SMA appear depending on the motor neuron pool, generally inversely related to SMN2 copy number. Cases with one SMN2 copy usually develop type 0 SMA, with cardiac malformation and arthrogryposis, anomalies potentially detectable during the prenatal period. Other problems, such as severe hypotonia, weakness, respiratory insufficiency and vascular issues, are noted at birth as part of congenital SMA. In fetuses with two SMN2 copies, predicted to have type I disease, it has been demonstrated that pathology is present in the prenatal period, although the consequences usually manifest after birth (<3 months). Fetuses with three and four copies may produce SMN above the threshold for prenatal pathology (horizontal dotted blue line), and thus disease may develop and manifest just in the postnatal period, usually after several months of life (>6 months in type II, >18 months in type III disease). Patients with four copies may remain without symptoms for several months or years. Predicted prenatal levels of SMN are represented according to SMN2 copy number. Levels after birth represent the evolution according to natural history.^, m = months; SMN = survival motor neuron protein.

Figure 2

Evolution of clinical stages in spinal muscular atrophy babies with two SMN2 copies from fetal stage to postnatal period. Most fetuses with spinal muscular atrophy (SMA) and two copies of SMN2 are predicted to have severe type I disease with prenatal initiation of neuropathology. In cases detected by newborn screening, the three main stages observable are clinically silent—presymptomatic, prodromic and fully symptomatic. The disease evolution between stages occurs by phenotransition in the first case and phenoconversion in the second. In patients with three SMN2 copies, the clinically silent phase varies but is typically at >3 months in duration and may be extended over years in four-copy individuals. Based on Finkel and Benatar and Tizzano and Zafeiriou.

Figure 3

Various approaches to treat spinal muscular atrophy (SMN-dependent and SMN-independent) could be complementary. Data from clinical trials and clinical practice will be used to assess whether a multi-pronged approach results in beneficial effects. See Table 1: Clinical trials, for combination therapies currently investigated in spinal muscular atrophy (SMA). At present, combination therapy has yet to be experimentally investigated in the prenatal stage in terms of clinical research. SMN = survival motor neuron protein. Created in BioRender. Tizzano, E. F. Lindner, G. (2025) https://BioRender.com/o5kmjq7.