Genetic Therapy in Neonatal Neurology—The Two-Edged Sword of Remarkable Benefit at Very High Cost—Infantile Spinal Muscular Atrophy as an Instructive Example

January 2025

Introduction

Many pediatric disorders caused by genetic abnormalities have been described in detail for many years. Therapies for such disorders have ranged from drugs to alter or correct affected biochemical pathways to transplantation of affected organs, e.g., liver, bone marrow, etc., to recover defective functions. Few such therapies have had long-lasting success. In recent years, replacement or correction of defective genes has been accomplished for many disorders and has drastically changed the outlook of patients with previously untreatable disorders. In pediatrics, several FDA-approved therapies have been generated for such diseases as sickle cell disease, Duchenne muscular dystrophy, an inherited retinal disorder, hemophilia A, β-thalassemia, leukemia/lymphoma, cerebral metachromatic leukodystrophy, and spinal muscular atrophy (SMA).¹ To my knowledge, only the severe form of SMA, type 1 SMA (see later), has been approved for neonatal treatment and will be the example chosen for this discussion of gene therapy in neonatal neurology.

Introduction to Type 1 SMA

In the following, I will outline briefly the principal clinical and molecular genetic features of type 1 SMA, the three major types of genetic interventions for this disorder and their associated outcomes, the importance of newborn screening and presymptomatic treatment, and the economic and ethical issues associated with the genetic therapies for type 1 SMA and, by extrapolation, for future genetic therapies for neonatal disorders.

Type 1 SMA—Clinical, Pathological and Genetic Aspects

Concerning clinical aspects, the disorder is clinically apparent at birth in 35%, in the first month of life in 16%, in the second month in 23%, and from the end of the second month to the sixth month of life in the remaining 26%.² Important for neonatologists, a careful  history usually reveals maternal report of decreased and weak fetal movements in the third trimester, and the initial neonatal exam notes, in nearly one-half, generalized weakness and hypotonia, weak cry, difficulty sucking and swallowing, but relative preservation of facial movement. The result is the very sad picture of a facially expressive but nearly motionless infant.

The neuropathology is distinctive and involves degeneration of anterior horn cells, secondary to deficiency of the protein, survival motor neuron (SMN). The biological functions of SMN involve RNA metabolism and thereby the assembly of multiple proteins, involved especially in axonal growth and maintenance.³ Spinal cord motor neurons are especially dependent on these proteins, because of the neurons’ very long axons and need for axonal mRNA transport and trafficking.⁴

The genetic defect in this autosomal recessive disorder involves the SMA region on chromosome 5.⁴ The region contains two copies of the SMN gene, one telomeric (SMN1) and the other, centromeric (SMN2). Homozygous deletions involving exon 7 of the SMN1 gene account for virtually all cases of type 1 SMA. The centromeric, SMN2 gene, contains a single nucleotide change in exon 7 that markedly influences splicing and, as a result, produces primarily 90-95% of a truncated protein, with a short life, and most importantly only approximately 5-10% of the normal full-length SMN protein.⁴ Notably, in the presence of the deleted SMN1 gene, SMN2 copy number may increase or decrease. The importance of this phenomenon is that the copy number of SMN2 is the most critical determinant of the severity of the SMA phenotype.⁴ In the most severe phenotype, i.e., type 1 SMA (the focus of this Commentary), approximately 80% of infants carry only one or two SMN2 copies. Two of the three genetic therapies to be described later lead to an increase in the amount of full-length SMN protein from SMN2.

Treatment of Type 1 SMA

In previous years, the principal treatments for type 1 SMA were supportive measures, focused on management of the impairments of sucking and swallowing and the handling of secretions. Thus, gastrostomy and, later, tracheostomy with invasive ventilation were needed to prolong life. Infants do not attain ability to sit, and without genetic therapy median age at death (or permanent ventilation) has been in the range of 4 to 8 months, with maximum survival rarely exceeding 12 to 18 months.^4,5

In recent years, genetic therapies have markedly altered the outcome of type 1 SMA. The three approaches include: (1) a single intravenous injection of a nonreplicating adenovirus that includes the normal SMN1 genetic sequence (onasemnogene abeparvovec [OA]),⁶ (2) repetitive intrathecal administration of the antisense oligonucleotide drug nusinersen that increases the amount of full-length SMN protein from SMN2, and (3) repetitive oral administration of a small molecule (risdiplam) that modulates SMN2 pre-RNA splicing and thereby increases the amount of full-length SMN protein from SMN2.

Although the detailed results of the multiple clinical trials carried out thus far with these three approaches are beyond the scope of this Commentary, overall the beneficial effects have been dramatic, as will be discussed briefly next (for reviews see^4,7-9).

Gene Replacement with OA

With gene replacement with OA, all symptomatic infants have survived, without need for permanent ventilation, and approximately one-half have achieved independent sitting by 18 months.⁷ (The ultimate duration of benefit from the single dose of OA is unclear.)

Notably, infants who are asymptomatic at the time of OA therapy and detected largely by newborn screening have had even better outcomes than when treated after the onset of symptoms (see Importance of Newborn Screening, later).^10,11 Thus, of 14 infants with two SMN2 copies infused with OA at a median age of 21 days, all survived and sat independently at 14 months, approximately 80% stood independently by 18 months and 64% walked independently by 18 months.

Nusinersen

Similarly, treatment with intrathecal nusinersen in symptomatic infants with type 1 SMA has led to markedly improved outcomes. In the initial major study by Finkel et al.,¹² 51% of the 73 nusinersen-treated infants had an impressive motor response (rolling over, sitting independently) versus none of the 37 controls. More strikingly, after these initial promising results in symptomatic infants, 15 type 1 SMA asymptomatic infants (with only 2 copies of SMN2), identified by newborn screening, were treated with nusinersen (median age at first dose: 19 days). The results were strikingly favorable: all were alive at follow-up at a median age of 4.9 years; all acquired independent sitting, 14/15 (93%) walked with assistance and 13/15 (87%) walked independently.¹³

Risdiplam

Although experience with oral risdiplam is less extensive than with OA and nusinersen, the drug has proven to be very effective. Initial work with 41 symptomatic infants with type 1 SMA treated for at least 12 months showed clear benefit—after 24 months, 83% were alive with no permanent ventilation, 61% were able to sit without support and 95% were able to feed orally.¹⁴ Importantly, recent experience with four infants treated presymptomatically (< 6 weeks) and followed for > 12 months showed that all infants survived and sat independently, and 2 of 4 stood independently.¹⁰ Follow-up is ongoing.

Importance of Newborn Screening

As noted in the previous section, considerable data now show that onset of any of the three treatment modalities prior to the development of clinical symptoms is associated with better outcomes when compared to treatment begun after such development.¹⁰ SMA was added to the US Federal Recommended Uniform Screening Panel for newborn screening in 2018 and currently approximately 99% of US newborns are screened.⁷ The disease incidence in the USA is approximately 1 in 1100.⁷ In 2023, the number of births in the US was 3,591,328.¹⁵ Thus, at least 330 new cases of SMA can be expected to be detected yearly. Moreover, because the disorder may be clinically silent in the newborn period, the neonatologist is likely to face the issue of discussing complex treatment options with a family unaware that their infant has a fatal disorder. As important, onset of whichever of the three treatment options is chosen should occur as promptly as possible, i.e., before the infant becomes symptomatic. As noted in the previous section, outcome is less favorable if the disease has become symptomatic prior to treatment, presumably reflecting more advanced degeneration of anterior horn cells.

Economic and Ethical Issues of Genetic Therapies—SMA as a Prime Example

Assessment of the economic and ethical issues of genetic therapies for type 1 SMA is of general importance, since the issues are relevant to current and future such therapies. Of particular importance in this context, with the broader impact of newborn screening and the importance of presymptomatic therapy, the neonatologist will be at the vanguard of prompt and carefully targeted therapy. Economic and ethical issues are closely intertwined because of the high cost of the therapies and issues related to the long-term durability of the therapies. In the brief discussion that follows, I will address economic issues first.

Economics of Genetic Therapies for Type 1 SMA—Costs

The economic costs of the three modalities, i.e., OA, nusinersen and risdiplam, are startling. For OA, the adeno-associated virus based gene delivery of a cDNA version of the SMN1 gene (FDA-approved for newborns in 2019), the cost is $2,125,000 for the single dose required.¹⁶ Durability of effectiveness appears to be good, at least over the 5+ years of follow-up thus far.

For nusinersen (FDA-approved for newborns in 2017), administered intrathecally initially as four loading doses every two months, and subsequently every 4 months, at $125,000 per dose, the cost therefore is $750,000 for the first year and then $375,000 per year subsequently.¹⁶ Durability of benefit is apparent over approximately 5 years of follow-up.

For risdiplam (FDA-approved for newborns in 2022), the cost is $100,000 to $340,000 per year, depending on the weight of the infant.¹⁶ Data thus far suggest that the agent is safe and effectiveness is durable, although experience with newborns and very young infants is limited.

A discussion of reported side-effects of these agents is beyond the scope of this Commentary. A reasonable conclusion currently is that the interventions are generally safe over the long term, and as noted earlier, the clinical benefit is enormous. Nevertheless, although durability of benefit appears good for the three therapies, data are relatively limited, follow-up is not long and later development of side effects are important unknowns.

Other Costs Related to Type 1 SMA

Families of infants with SMA bear enormous costs related to the infant’s health care expenses (other than genetic therapies), loss of family income, expenses for daily caregivers, etc. In one careful analysis in Australia, such annual costs amounted to approximately US$230,000, with substantial deficits in health-related quality of life for both affected infants and their caregivers.¹⁷ Although data are still relatively limited, available information from several countries indicates that presymptomatic screening and early therapy have enormous benefits on economic costs and quality of life for both patients and families.^16-19

Paying for Genetic Therapies for SMA

Payment for the three genetic therapies outlined earlier is an enormous challenge, both in countries like the United States with mixed private and government insurance and in countries with completely government-paid health care. In the United States, coverage varies among insurers. Currently, the three drug companies involved in the SMA treatments just described have co-pay programs, as well as referrals to charitable organizations for third-party assistance.¹⁶ Medicare and Medicaid are a third source of payment. In 2018, nusinersen alone cost Medicaid an estimated $150,000,000 to $189,000,000.²⁰ Among the potential solutions to the challenge of the high cost of genetic therapies is the over-arching need both to control costs and to assure access to affected infants. Medicaid appears to be the modality with sufficient power to negotiate with drug companies to assure access for affected infants.²⁰ The great unknown at present in the United States is whether those with governmental oversight of Medicare and Medicaid will pursue this course.

The economic issues associated with genetic therapies for SMA are, in many ways, “the canary in the coal mine” concerning future genetic therapies. Although currently only 8 such therapies have received FDA approval for pediatric patients, the issue is nearly at an explosive stage. Thus, examination of the pipeline for such therapies shows that approximately “85 new gene therapies across more than 12 therapeutic areas are expected to receive regulatory approval by 2032, with an estimated ten-year list price of $35 billion to $40 billion.”²¹ Many of these are likely to be applicable to the newborn.

Ethical Issues of Genetic Therapies for Type 1 SMA

To consider the ethical issues raised by the genetic therapies for type 1 SMA, Yeo et al.¹⁶ use as a guiding principle weighing the needs of the individual against the needs of the collective of society. The intersection of the economic issues with societal needs is clearly a major point of tension. However, with all three drugs, especially with presymptomatic treatment, it appears thus far with type 1 SMA that an infant who would have died over months now can survive with normal or near normal development. Apart from studies of quality-of-life measures which show the pronounced economic savings for society with these genetic therapies, the apparent durability of their benefit, and their apparent safety, it is difficult to imagine any other course but to find, by whatever means, a way to treat the afflicted child. As caregivers for these infants, our role should expand beyond that of diagnosis of the disorder and dealing with the life-threatening events of the afflicted child. Our role needs to extend to advocacy for access of our infants to the latest successful gene therapies. It would be hard to imagine a greater stimulus for such advocacy than to enable a beautiful but paralyzed infant, destined to die in months, to receive a genetic therapy that provides the promise of normal development and great happiness for a family.

Summary / Conclusions

The focus of this Commentary has been genetic therapy in neonatal neurology, with SMA as the illustrative example. The therapies include direct infusion of the normal gene that is defective in SMA, repetitive intrathecal administration of an antisense oligonucleotide drug that increases the amount of the normal gene product, and oral administration of a drug that modulates RNA splicing and thereby increases the amount of the normal gene product. Results have been remarkably favorable, and especially with presymptomatic treatment afforded by newborn screening, normal development seems achievable.

The great promise of these therapies occurs in the context of their remarkable financial expense. The resulting economic and ethical issues are a great challenge to society, on multiple levels. Nonetheless, in my view the success of the genetic therapies for SMA and the likelihood that such therapies for other neonatal neurological disorders, e.g., metabolic, degenerative, neuromuscular, etc., are on the horizon make it clear that our role as neonatal caregivers must expand to societal advocacy for universal access.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

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