Fetal Therapy Could Offer a Lifeline for Children With Genetic Disorders

Genetic disorders with onset before birth are a leading cause of death in infants and children. Thanks to advances in imaging and genetic diagnostic technologies, clinicians can now detect many of these disorders in the womb. This has opened the door to fetal therapies that allow clinicians to intervene before irreversible damage occurs.

Fetal therapies have evolved from invasive open surgical procedures to investigational therapies that utilize advanced technologies such as stem cells and gene editing. This transformation has drastically changed the possibilities for treating genetic disorders in utero.

Intervening before birth could preempt early organ damage and improve perinatal outcomes. Natural fetal immune tolerance, coupled with high cellular turnover, could even enhance therapeutic impact.

Despite the many potential benefits of fetal therapies, there has historically been a lack of appetite among pharmaceutical companies to invest in research for therapies that are used during pregnancy. This is often rooted in fears of maternal-fetal complications, lack of guidance on how to conduct clinical trials involving pregnant women, and the legal implications of treating both fetus and mother simultaneously. Against this backdrop, can fetal therapy redefine the standard of care for rare genetic disorders?

A new era for fetal therapies

Key drivers advancing fetal therapies towards the clinic include developments in prenatal imaging and next-generation sequencing (NGS), which have enabled clinicians to identify and characterize genetic disorders in utero.

“Improvements in 3D USS [ultrasound] and MRI [magnetic resonance imaging] (especially super-resolution reconstruction techniques for MRI) are improving our ability to make an informed prenatal diagnosis,” Prof. Anna David, a professor of obstetrics and maternal fetal medicine at University College London (UCL), told Technology Networks.

Advances in imaging have not only improved diagnosis but have also enabled the safe delivery of therapeutics to the fetus. “With current ultrasound technology, it is very straightforward and extremely safe to administer drugs, as well as cell and gene therapies, to the fetus by a simple percutaneous injection, similar to amniocentesis,” Prof. Graça Almeida-Porada, a professor of regenerative medicine at the Wake Forest Institute for Regenerative Medicine, told Technology Networks.

These improvements, combined with the ability to use NGS approaches during pregnancy, such as gene panels, exome sequencing, and whole genome sequencing, mean it's now possible to detect a range of rare genetic disorders in the womb.

Alongside improved diagnostics, therapies themselves are advancing. In gene therapy, new vectors and more targeted delivery technologies are being developed, leading to safer and more precise therapeutics.

“Gene editing platforms have advanced tremendously in recent years, as the field has moved from CRISPR/Cas-based editing that requires induction of double-strand breaks within the DNA to base editors, and more recently to the most advanced platform prime editors,” Prof. Christopher Porada, a professor at the Wake Forest Institute for Regenerative Medicine, told Technology Networks.

“As the field has evolved, each new technology has become more precise and has promised ever-higher specificity with a lower risk of off-target effects. Each of these improvements in the safety and precision of gene editing has brought the possibility of using such treatments in the fetus closer to clinical reality,” Porada continued.

Deadly disorders treated in utero for the first time

Technological advances in prenatal diagnostics and treatment aren’t just theoretical. An increasing number of real-world cases are emerging of fetal therapies being used to treat patients in the womb. In February 2025, it was reported that a child diagnosed with spinal muscular atrophy (SMA) had no identifiable features of SMA two years after in utero treatment with the small molecule drug risdiplam.

SMA is caused by recessive loss-of-function mutations in the SMN1 gene, leading to a lack of the survival motor neuron protein. This protein is important for development, particularly in the third trimester and the first three months after birth. Early intervention is therefore critical to managing symptom severity. The risdiplam case study demonstrates the safety and feasibility of treating SMA in utero using an orally administered drug.

The same year, a team of researchers found that antisense oligonucleotides (ASOs) delivered via amniotic fluid injection could improve treatment outcomes of SMA in mouse models. The ASOs restore production of full-length SMN protein by repairing the splicing of the mRNA encoded by the SMN2 gene, which is retained in SMA patients but normally produces only truncated, nonfunctional SMN protein. The researchers are now looking to optimize the ASOs to find one suitable for clinical trials.

Outside of rare genetic disorders, gene therapy approaches have also been proposed to treat fetal growth restriction (FGR), using adenoviral vectors. “The gene therapy that we are proposing is a short-term increased expression of the VEGF protein locally in the uteroplacental circulation,” said David. “Gene therapy allows a targeted approach in this condition, where we know that there is reduced availability of the VEGF protein at the level of the uterine circulation.

“Early studies in two preclinical models of FGR have shown that this approach increases fetal growth without any evidence of harm to the fetus, neonate, or mother. There is a spread of the vector to the maternal tissues, especially the liver, where the vector is broken down. But importantly, there is no spread to the fetal tissues, especially none in the fetal gonads, which is reassuring for safety.”

David and colleagues have since interviewed stakeholders and parents who have experienced severe early-onset FGR about the possibility of a clinical trial of maternal VEGF gene therapy. “The response was positive, with parents especially welcoming a potential treatment to improve their baby’s outcome,” David said.

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Beyond gene therapy, fetal stem cell therapies that leverage the functional immaturity of the fetal immune system hold promise. “At UCL, we are developing gene editing approaches to correct fetal stem cells ex vivo, using amniotic fluid stem cells collected via amniocentesis and then injecting the gene-corrected cells back into the fetus for therapeutic effect,” said David.

In utero stem cell approaches have the advantage of targeting cells or organs inaccessible in adult life, while avoiding sequestration of stem cells in the lungs after injection into the umbilical vein. In addition, the small size of the fetus reduces the number of stem cells required for treatment.

“The biology of the fetus makes it a far better recipient for cell and gene therapy than an adult, child, or even an infant,” explained Almeida-Porada.

“Many barriers that preclude efficient drug and gene delivery in the postnatal patient (e.g., the blood-brain-barrier, the mucous barrier in the airway, specifically in the setting of cystic fibrosis) are either not present or are still forming, allowing efficient delivery of therapeutics to these cells/tissues,” Almeida-Porada stated.

“The fetus is also suspended in amniotic fluid, which it is constantly swallowing/breathing during development. This serves as a unique and facile delivery route for therapeutics that need to reach the airways and the GI tract.”

Enzyme replacement therapy—whereby functional, manufactured enzymes are administered to a patient to replace missing or deficient enzymes—also holds promise as a fetal therapy. A study, published in the New England Journal of Medicine, reported successful treatment of infantile-onset Pompe disease by initiating enzyme replacement therapy during fetal development. The child, Ayla, was given six prenatal enzyme replacement treatments. As a result, Ayla was born at term and at 16 months of age was reported to have normal cardiac and motor function.

Clinical trial challenges hold back progress

Despite promising results in preclinical models and case studies, moving fetal therapies into clinical trials has required years of work. One of the challenges was the lack of definitions for what constitutes an adverse event in the mother and baby.

David now believes this challenge has been addressed: “When we first looked at how to assess safety, such as adverse events in clinical trials, we were shocked to discover that the usual terminology systems, such as CTCAE [Common Terminology Criteria for Adverse Events] or DAIDS [Division of AIDS], only had a handful of adverse event definitions for maternal or fetal complications that might result from drug treatments. This meant that it was impossible to accurately assess the safety of any intervention—be it drug or device—in pregnancy.”

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Maternal Fetal Adverse Event Terminology [MFAET] was launched by David and team in 2021 with 38 new definitions of safety signals observed in the mother and fetus. David explains that this is the “first and only terminology to address improving the safety of clinical trials in pregnancy, describing adverse events in the mother and fetus.”

Not only has a lack of definitions held back clinical trial progress, but Porada believes that “the preconceived notion that treatments must first be tested in adults, then in children” has plagued the advancement of fetal cell and gene-based therapies.

“While this paradigm of testing first in adults often works when trying to develop therapeutics for adolescents, and in some cases for children, it is often completely invalid in the case of in utero therapies, which are specifically designed to be age-bespoke, taking advantage of the distinctive physiology and immunology of the fetal recipient, and the unique opportunities they create,” said Porada.

Even with these barriers, progress has been made, and today, various clinical trials are underway to investigate the effects of fetal therapies. “At present, in utero stem cell transplantation has already been performed, on a compassionate use basis, on over 50 human patients for more than a dozen genetic disorders, and 3 clinical trials are being performed,” stated Almeida-Porada.

The next steps for fetal medicine

The outlook for fetal therapies is improving thanks to emerging tools for prenatal diagnosis. Porada envisions that further advances in digital PCR could pave the way for the validation and widespread acceptance of prenatal diagnosis for most genetic disorders. This could be performed by drawing blood from the pregnant woman and analyzing the cell-free fetal DNA present.

“The availability of safe, non-invasive prenatal testing/diagnosis will surely fuel the development of treatments for the diseases that can be identified early in gestation,” Porada said.

While resistance still exists to the application of gene-based therapies to fetal recipients, further advances in cell-targeting and specificity could help overcome uncertainties regarding the risk of off-target effects.

More robust data on the mutagenesis risk will allow regulatory agencies to make more informed risk-to-benefit calculations when evaluating proposed trials using these therapies. The path to getting these therapies into the clinic may be difficult. But Almeida-Porada hopes that “ongoing trials will help to change the entire paradigm for how we diagnose and treat most genetic disorders within the coming years.”