Spinal muscular atrophy, a genetic condition caused by insufficient levels of survival motor neuron (SMN) protein, results in the loss of motor neurons in the spinal cord, rendering patients unable to control voluntary movements. Current interventions involve administration of antisense oligonucleotides (ASOs) that manipulate RNA splicing to increase functional SMN protein, but these therapies are typically delivered postnatally and have limited efficacy once irreversible neural damage has occurred. The UCSF-led team sought to explore if earlier delivery of ASOs directly into the fetal environment could halt disease progression preemptively.

In a sophisticated series of experiments, researchers injected ASOs into the amniotic fluid of pregnant mice genetically engineered to model SMA. The prenatal administration led to substantial improvements in offspring survival rates, motor function, and preservation of spinal cord motor neurons, markedly outperforming mice treated only after birth or untreated controls. These results offer compelling evidence that manipulating gene expression at the earliest developmental stages can significantly alter disease trajectories.

To verify the safety and biodistribution of this intra-amniotic delivery method, parallel investigations were conducted in healthy sheep. Using fluorescently labeled ASOs, the team traced the molecules’ association within the fetus after amniotic injection, revealing widespread distribution to key organs including the brain, spinal cord, lungs, and gastrointestinal tract. Importantly, no toxic effects or adverse developmental outcomes were noted, underscoring the potential clinical feasibility of this minimally invasive approach.

One of the most remarkable findings was the natural fetal behavior facilitating therapeutic uptake: the fetuses inhaled and swallowed the ASOs suspended in the amniotic fluid, enabling systemic delivery without reliance on direct vascular injection. This “inverse amniocentesis” concept overturns traditional prenatal sampling methods, suggesting an innovative outpatient procedure wherein physicians inject medication into the amniotic cavity, which the fetus then internalizes over time through natural swallowing and breathing movements.

ASOs function by selectively binding to RNA transcripts, modulating splicing patterns to restore or enhance production of critical proteins. The UCSF study employed these synthetic nucleotide sequences to target the SMN2 gene, a paralog of the defective SMN1 gene in SMA, prompting increased generation of the essential survival motor neuron protein. This mechanism of RNA-based therapeutic modulation has revolutionized treatment for genetically rooted neurodegenerative diseases but had not been previously trialed in the prenatal setting at this scale and depth.

The translational potential of this research is significant because it aligns with ongoing improvements in prenatal diagnostics, where genetic screening can identify SMA and other genetic conditions with high sensitivity during gestation. Delivering effective molecular therapies intra-amniotically during critical windows of fetal development could reduce or eliminate irreversible damage that standard postnatal treatments struggle to address.

While prior investigations have explored ASO administration to adult or neonatal subjects, as well as intra-amniotic ASO delivery in small animal models for related disorders like Angelman and Usher syndromes, this study is the first to evaluate prenatal ASO treatment in large animal models. The collaboration across UCSF, UC Davis, Johns Hopkins, Cold Spring Harbor Laboratory, and industry partners Ionis Pharmaceuticals and Biogen was pivotal in achieving the rigorous preclinical benchmarks necessary for future regulatory approvals.

The team’s next ambitious step involves applying to the U.S. Food and Drug Administration (FDA) for approval to initiate clinical trials of prenatal ASO treatments in humans. Such trials will need to demonstrate not only therapeutic efficacy but also stringent safety profiles, particularly regarding systemic distribution, duration of effect, and avoidance of fetal toxicity. The encouraging findings from both mice and sheep models provide a solid foundation upon which to build.

This breakthrough sits at the crossroads of precision medicine, developmental biology, and gene therapy, highlighting the power of targeted molecular interventions within the womb to alter lifelong health outcomes. It illustrates a transformative vision where debilitating genetic diseases identified before birth can be intercepted and mitigated during early development rather than managed post-onset.

The feasibility of an outpatient, low-risk injection procedure akin to traditional amniocentesis enhances the clinical appeal and accessibility of this approach. It promises a paradigm shift in fetal medicine, empowering physicians to deliver personalized therapeutics directly within the fetal environment with minimal invasiveness and maximal impact.

Moreover, the researchers speculate that the amniotic fluid delivery platform could be adapted beyond SMA to address other severe, early-onset genetic disorders affecting various organ systems. The exact mechanisms of ASO distribution observed suggest potential targeting of neurological, pulmonary, gastrointestinal, and nasal tissues, broadening the therapeutic scope of this approach.

This work exemplifies the profound innovation arising from multidisciplinary partnerships spanning academic institutions and biotechnology companies. By combining expertise in fetal surgery, molecular genetics, pharmacology, and animal modeling, the team has laid essential groundwork for ushering in a new era of prenatal gene therapies.

Ultimately, this study heralds a future in which antenatal molecular interventions could drastically reduce the burden of genetic diseases, improving survival and quality of life for countless affected individuals. Continued research, regulatory advancement, and carefully designed clinical trials will be key to translating these promising preclinical findings into standard clinical practice.

Subject of Research: Prenatal treatment of spinal muscular atrophy using antisense oligonucleotides delivered via amniotic fluid injection

Article Title: (Not provided)

News Publication Date: (Not provided)

Web References: (Not provided)

References: Study published in Science Translational Medicine

Image Credits: (Not provided)

Keywords: Genetic disorders, Amniocentesis, Uterus, Spinal muscular atrophy, Oligonucleotides, RNA, Pediatrics, Umbilical vein, Motor neurons, Pregnancy, Scientific collaboration

Dr. Finkel’s tenure at St. Jude symbolizes a crucial evolution in pediatric medicine. CENT represents the clinical wing of the Pediatric Translational Neuroscience Initiative (PTNI), an innovative research platform focused on turning laboratory discoveries into tangible clinical interventions for catastrophic neurological diseases. By integrating cutting-edge neuroscience with clinical application, CENT aims to address urgent unmet needs in pediatric neuromuscular disorders, including spinal muscular atrophy (SMA), Duchenne muscular dystrophy, inherited neuropathies, and neurometabolic disorders. This expansion aligns with St. Jude’s broader vision to extend its decades-long legacy of curing childhood cancer to crippling neurologic diseases.

Among Dr. Finkel’s most notable clinical achievements is his leadership in conducting the first in utero treatment of spinal muscular atrophy using risdiplam, an orally administered drug. SMA is a genetic neuromuscular disorder characterized by progressive muscle wasting and weakness due to the degeneration of motor neurons. Traditionally diagnosed postnatally, SMA results in severe disability or death if untreated. Dr. Finkel’s prenatal intervention represents a revolutionary paradigm shift in treatment, leveraging the prenatal environment’s unique immunological and developmental properties to arrest disease progression even before birth.

This landmark in utero treatment, performed in 2022, demonstrated remarkable efficacy. The infant treated prenatally with risdiplam showed no detectable manifestations of SMA over two years after birth, a stark contrast to the expected clinical trajectory of untreated SMA patients. The underlying mechanism involves risdiplam’s ability to increase the production of survival motor neuron (SMN) protein by modifying the splicing of the SMN2 gene, thereby compensating for the loss of function mutation in SMN1. Administering the therapy during fetal development maximizes the preservation of motor neuron populations before irreversible degeneration occurs, highlighting the critical window that prenatal therapy opens for neurodegenerative diseases.

Published in a letter to the New England Journal of Medicine in early 2025, these findings provide robust proof of concept for prenatal intervention as a viable therapeutic strategy. This study not only underscores the biological plausibility but also opens new investigative avenues for other genetic neuromuscular disorders traditionally treated postnatally or symptomatically. The clinical outcomes have profound implications for developmental neurobiology, pharmacokinetics in utero, and fetal immune tolerance mechanisms, which collectively influence the safety and efficacy of early pharmacological intervention.

Dr. James R. Downing, president and CEO of St. Jude Children’s Research Hospital, emphasized that Dr. Finkel’s designation as a TIME100 Health honoree illuminates the significance of pioneering pediatric neuromuscular diseases that have historically been underserved. His work encapsulates the hospital’s expanding commitment to eradicate not only life-threatening cancers but also the devastating neurological disorders that compromise childhood development and survival worldwide. This recognition amplifies ongoing efforts to develop therapies that provide durable, disease-modifying benefits, substantially improving quality of life for affected children.

The research implications of Dr. Finkel’s work extend beyond SMA into a broad spectrum of neurological diseases caused by genetic mutations, neurodegeneration, and metabolic imbalances. His extensive clinical practice focuses on optimizing therapeutics involving gene modulation, neurometabolic stabilization, and neuroprotective strategies. By combining clinical acumen with translational neuroscience, Dr. Finkel accelerates the bench-to-bedside pathway, enabling novel interventions to move rapidly through preclinical models to clinical trials and eventually standard of care.

Over his distinguished career, Dr. Finkel has authored more than 150 peer-reviewed articles and book chapters, reflecting his deep scientific insight and commitment to collaborative neurology research. He has played an instrumental role in designing innovative clinical trials that incorporate biomarkers, electrophysiological metrics, and advanced imaging to measure therapeutic efficacy objectively. His approach exemplifies precision medicine tailored to the unique genetic and phenotypic profiles of pediatric patients suffering from debilitating neuromuscular disorders.

The success of in utero therapy for SMA challenges existing paradigms of treatment timing and delivery, suggesting that early intervention—potentially initiated during gestation—could prevent irreversible neurological damage more effectively than postnatal treatments. This has profound implications for future drug development targeting other monogenic neurological conditions, advocating for the integration of prenatal diagnostic tools and therapeutic planning into neonatal care. This clinical innovation could dramatically shift global health policies around fetal medicine and pediatric neurology.

Dr. J. Paul Taylor, executive vice president and scientific director at St. Jude and director of PTNI, pointed out the critical unmet clinical need in catastrophic neurological diseases, areas where research has lagged behind oncology. Unlike cancer or sickle cell disease, many neurological disorders have lacked effective disease-modifying therapies. The translational neuroscience platform led by Dr. Finkel is transforming this landscape by combining molecular biology, genetics, and pharmacology to exploit new therapeutic targets and innovative delivery systems, including oral small molecules such as risdiplam.

St. Jude Children’s Research Hospital’s historic mission has evolved from groundbreaking pediatric oncology to embracing complex neurological diseases, leveraging its multidisciplinary expertise and infrastructure. The hospital remains a world leader in pediatric biomedical research, integrating genomic sequencing, cellular biology, and clinical trials to foster therapeutic development. By sharing discoveries openly with global collaborators, St. Jude ensures advances benefit children worldwide, supporting a collaborative, data-driven approach to medicine.

In conclusion, Dr. Richard S. Finkel’s recognition as a TIME100 Health honoree is a testament to his visionary leadership and translational impact in pediatric neurology. His achievements in prenatal treatment for SMA represent a transformative milestone that reshapes how we understand, diagnose, and treat genetic neuromuscular disorders. With ongoing clinical and scientific efforts, Dr. Finkel and the St. Jude team continue to push the boundaries of pediatric neurotherapeutics, offering hope and healing to children and families facing devastating neurological diseases.

Subject of Research: Pediatric Neuromuscular Disorders, Prenatal Therapy for Spinal Muscular Atrophy
Article Title: Richard S. Finkel Named to TIME100 Health 2025 for Pioneering Prenatal Treatment of Spinal Muscular Atrophy
News Publication Date: 2025
Web References:

• https://time.com/collections/time100-health-2025/7279665/richard-finkel-kelly-hennings/?filters=pioneers
• https://www.stjude.org/directory/f/richard-finkel.html
• https://www.stjude.org/research/initiatives/pediatric-translational-neuroscience-initiative.html
• https://www.stjude.org/care-treatment/treatment/neurological-disorders/spinal-muscular-atrophy.html
• https://www.stjude.org/media-resources/news-releases/2025-medicine-science-news/promising-results-from-first-prenatal-therapy-for-spinal-muscular-atrophy.html

Image Credits: St. Jude Children’s Research Hospital

Keywords: Spinal muscular atrophy, Neurology, Neurological disorders, Pediatrics, Neuropathology