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Gene Therapy For Inherited Disease In The Unborn Child

Until recently, even the most advanced gene therapies could only be given after a child was ... More born—often racing against time to prevent irreversible damage.

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In the first part of this series, we explored how early genetic screening and gene therapy transform the lives of newborns and their families. Now, we're taking an even earlier step: treating inherited diseases in the womb before birth. Until recently, even the most advanced gene therapies could only be given after a child was born—often racing against time to prevent irreversible damage. But what if we could intervene even earlier?

That's the question now being answered, with some astonishing results. A recent study published in Science Translational Medicine showed that delivering a special kind of genetic therapy directly to the fetus could prevent the onset of spinal muscular atrophy in animal models. Treating the condition before birth may be possible to preserve healthy motor function and prevent the nerve damage that usually begins in the womb. This is the first time we see molecular therapies targeting the root cause of inherited disease before birth.

Another special investigational case, the first in humans, found that providing the mother with gene therapy while pregnant and continuing treatment after birth also prevented the devastating muscle weakness that usually comes with the disease. This is a true leap forward: instead of managing symptoms; we may soon be able to stop some inherited diseases before they ever begin.

Treating Inherited Disease Before Birth

The journey starts with advanced prenatal genetic screening. Genetic changes in the developing fetus can be found using a simple blood sample from the mother. When a risk is found, therapy is delivered directly to the fetus, often by injecting medicine into the amniotic fluid. In the case of spinal muscular atrophy, this approach in animal models led to healthier development and longer survival. These findings suggest that intervening before birth can prevent or significantly reduce the neurological damage that begins in the womb and progresses rapidly after birth.

While most of this research has been in animals, the first human steps have already begun. In February 2025, the University of California, San Francisco, reported the world's first attempt to treat a genetic disease in a human fetus using a medication called risdiplam. After learning that her unborn child was at risk, a mother began taking the medication late in pregnancy. The baby was born healthy and—now more than two years old—shows no signs of the disease, though some developmental challenges remain.

Another important step was taken in a clinical trial at UCSF, where doctors successfully treated a fetus with a different rare disease using enzyme replacement therapy, showing that the technology for delivering medicine to the unborn is already here.

Why Does This Matter?

Many inherited diseases cause the most significant harm before a baby is even born. By intervening early, we have the chance to save lives and give children the best possible start—preserving their ability to move, think, and grow. This isn't just a medical advance. It's a new way of thinking about what's possible for families facing genetic disease.

Of course, there are still challenges ahead. Many are working to ensure these therapies are safe, effective, and accessible to all who need them. Ethical questions about when and how to use these powerful tools will also need careful thought. The first human applications of gene therapy before birth are expected within the next decade, pending rigorous safety and ethical evaluations. This new era also brings new questions. If we correct a genetic error in a child before birth, will that change be passed on to future generations?

For now, most therapies target the body's somatic cells, not the germline, so the changes are not inherited. However, the line between somatic and germline interventions may blur as technology evolves, raising complex ethical considerations.

Looking Forward: Prevention, Not Just Treatment

The first human trials of in-utero gene therapy are just beginning, and more research is needed. But the direction is clear: as technology advances, we are moving from treating inherited diseases after birth to preventing them at the start of life.

As I have often said, the future of medicine is being rewritten, one gene at a time. This latest breakthrough brings us one step closer to a world where prevention, rather than treatment, becomes the standard for genetic disease, where every child can live their healthiest life from the very start. As discussed in my book, the hope is that every child will soon have the chance to live their healthiest life from the beginning.


Polycystic Kidney Disease: Causes, Treatments, And What's Ahead

Polycystic Kidney Disease (PKD) is a progressive inherited disorder that causes many cysts, not just fluid filled cysts, to form in the kidneys and ultimately impair their function. PKD is a genetic disease and genetic disorder caused by gene mutations passed from biological parents to their children.

There are two main types of PKD: autosomal dominant PKD (ADPKD) which is the most common and autosomal recessive PKD. The disorder affects men and women equally. Over time these cysts can grow, replace normal kidney tissue and lead to end stage kidney disease (ESKD).

Risk factors for PKD include having an affected parent as the condition is inherited and other genetic variables. PKD can also lead to serious complications beyond kidney failure such as pre-eclampsia and aneurysms.

As we learn more about the genetic and molecular basis of PKD – particularly ADPKD – research is starting to shape more targeted treatments and patient centered care models.

Table of ContentsGenetic and Molecular Mechanisms

PKD is driven by mutations in two genes: PKD1 and PKD2 which encode the proteins polycystin-1 and polycystin-2. These proteins are crucial for the structure and function of kidney tubules. When they malfunction kidney cells start to divide abnormally and secrete fluid leading to cyst formation and kidney enlargement.

Autosomal recessive PKD (also known as autosomal recessive polycystic kidney disease) is a rarer form of PKD caused by a genetic fault that occurs when both parents carry the abnormal gene and pass it on to their child.

According to a 2014 review in Wiley Interdisciplinary Reviews: Developmental Biology [1] polycystin-1 is a mechanoreceptor – essentially a sensor that helps kidney cells respond to fluid flow. A 2004 study deepens this understanding by showing polycystin-1's role in complex cellular signaling [2].

More recent research in Physiological Reviews (2025) looks at the primary cilium – a tiny antenna-like structure on kidney cells. This cilium helps sense mechanical changes in fluid flow and interacts with polycystins and another protein fibrocystin all of which are essential in preventing cyst development [4].

Disruption of normal development of the kidneys and liver is a hallmark of autosomal recessive PKD as the genetic fault interferes with the organs' typical growth and function. While the exact mechanics are still being studied it's clear that disturbances in this cellular machinery is at the heart of PKD pathology.

Genetic testing can identify mutations in PKD related genes such as PKD1, PKD2 or PKHD1 and help with diagnosis and family planning. A genetic counselor can help families understand inheritance patterns, the risks associated with autosomal recessive PKD and guide them through genetic testing and family planning decisions.

Intracellular Signaling Pathways and Therapeutic Targets

Beneath the genetic mutations are a set of signaling pathways that drive cyst growth. One key player is cyclic AMP (cAMP) which increases fluid secretion and cell proliferation; increased cAMP levels cause cysts to grow in the kidneys.

Other important pathways include epidermal growth factor (EGF) and AMP-activated protein kinase (AMPK) as noted in a 2021 review from Biochemical Society Transactions [5]. These molecules act like traffic signals for cell activity – when their function goes awry cysts can grow unchecked.

Another major breakthrough is on vasopressin receptors, especially V2. The drug called tolvaptan, currently the only FDA approved disease modifying therapy for ADPKD works by blocking these V2 receptors to reduce cAMP production and slow cyst expansion.

For ADPKD patients the drug tolvaptan can slow the rate at which cysts grow and delay disease progression. A 2025 study in the American Journal of Physiology confirms that blocking other receptors (V1a, V1b) doesn't provide added benefit refining our understanding of this treatment's specificity [11].

Clinical Practice and Guidelines

Modern PKD care is about early diagnosis, genetic counseling and personalized treatment. To diagnose PKD imaging tests such as ultrasound, computed tomography scan and MRI scans are used to detect and monitor cyst development. The 2020 Chinese clinical practice guidelines are a comprehensive resource for clinicians covering everything from risk stratification to long term monitoring and intervention strategies [3].

These guidelines build on earlier frameworks such as the 2018 Nature Reviews: Disease Primers article which bridges cellular biology with real world clinical application [6]. Meanwhile a 2017 review in Comprehensive Physiology helps contextualize both hereditary and sporadic forms of PKD and offers a deeper dive into how and why cysts form [9].

Patient Outcomes and Research Priorities

As treatment advances patient voices are becoming more central to shaping research priorities. A 2025 study in Kidney360 gathered insights from patients, caregivers and healthcare professionals and found that preserving kidney function, improving quality of life and managing related health conditions are top concerns [10].

PKD can have a big impact on mental health. Many patients experience emotional challenges such as depression and anxiety. Addressing these mental health concerns is essential for overall well being.

Healthcare providers play a crucial role in supporting patients by offering resources, guidance and referrals to mental health professionals when needed. Adopting a healthy lifestyle – staying active, reducing stress, quitting smoking and maintaining a healthy weight – can help manage PKD and related health conditions.

This shift towards value based, participatory care is a trend across nephrology – where patients are not just recipients of care but active collaborators in defining meaningful outcomes.

Gaps in Knowledge and Future Directions

Even with these advances there are still many questions:

  • What are the exact molecular functions of polycystins and fibrocystin?
  • Can we identify early biomarkers to predict which patients will progress rapidly?
  • Are there safer alternatives to tolvaptan, especially those that reduce its aquaretic side effects (excessive urination and thirst)?
  • Research is ongoing to prevent kidney damage and to avoid factors that can make kidney damage worse in PKD. PKD is one of many kidney diseases; for example acquired cystic kidney disease can develop in people with chronic kidney disease especially those on long term dialysis. Prevention of kidney failure is key for PKD patients.

    Historical perspectives from the 2009 Annual Review of Medicine and 2013 Minerva Urologica e Nefrologica show just how far we have come and how far we have to go [7] [8]. These reviews highlight the need for therapies that not only slow cyst growth but also reverse or repair the cellular defects that underlie PKD.

    Closing Thoughts

    Polycystic Kidney Disease is a complex condition rooted in genetic and cellular abnormalities that are slowly being uncovered by modern science. Advances in molecular biology, imaging and drug development have improved how the disease is diagnosed and managed.

    But long term success depends on closing the gaps in knowledge, refining the therapies and keeping patients at the centre of both clinical and research efforts.

    References

    [1] Paul, B. M., & Vanden Heuvel, G. B. (2014). Kidney: polycystic kidney disease. Wiley interdisciplinary reviews. Developmental biology, 3(6), 465–487. Https://doi.Org/10.1002/wdev.152

    [2] Wilson P. D. (2004). Polycystic kidney disease: new understanding in the pathogenesis. The international journal of biochemistry & cell biology, 36(10), 1868–1873. Https://doi.Org/10.1016/j.Biocel.2004.03.012

    [3] Writing Group For Practice Guidelines For Diagnosis And Treatment Of Genetic Diseases Medical Genetics Branch Of Chinese Medical Association, Xu, D., & Mei, C. (2020). Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics, 37(3), 277–283. Https://doi.Org/10.3760/cma.J.Issn.1003-9406.2020.03.009

    [4] Boletta, A., & Caplan, M. J. (2025). Physiologic mechanisms underlying polycystic kidney disease. Physiological reviews, 105(3), 1553–1607. Https://doi.Org/10.1152/physrev.00018.2024

    [5] Richards, T., Modarage, K., Malik, S. A., & Goggolidou, P. (2021). The cellular pathways and potential therapeutics of Polycystic Kidney Disease. Biochemical Society transactions, 49(3), 1171–1188. Https://doi.Org/10.1042/BST20200757

    6] Bergmann, C., Guay-Woodford, L. M., Harris, P. C., Horie, S., Peters, D. J. M., & Torres, V. E. (2018). Polycystic kidney disease. Nature reviews. Disease primers, 4(1), 50. Https://doi.Org/10.1038/s41572-018-0047-y

    [7] Harris, P. C., & Torres, V. E. (2009). Polycystic kidney disease. Annual review of medicine, 60, 321–337. Https://doi.Org/10.1146/annurev.Med.60.101707.125712

    [8] Czarnecki, P. G., & Steinman, T. I. (2013). Polycystic kidney disease: new horizons and therapeutic frontiers. Minerva urologica e nefrologica = The Italian journal of urology and nephrology, 65(1), 61–68. Https://pubmed.Ncbi.Nlm.Nih.Gov/23538311/

    [9] Ghata, J., & Cowley, B. D., Jr (2017). Polycystic Kidney Disease. Comprehensive Physiology, 7(3), 945–975. Https://doi.Org/10.1002/cphy.C160018

    [10] Mustafa, R. A., Kawtharany, H., Kalot, M. A., Lumpkins, C. Y., Kimminau, K. S., Creed, C., Fowler, K., Perrone, R. D., Jaure, A., Cho, Y., Baron, D., & Yu, A. S. L. (2025). Establishing Meaningful Patient-Centered Outcomes with Relevance for Patients with Polycystic Kidney Disease: Patient, Caregiver, and Researcher Priorities for Research in Polycystic Kidney Disease. Kidney360, 6(4), 573–582. Https://doi.Org/10.34067/KID.0000000695

    [11] Wang, X., Jiang, L., Nanayakkara, K., Hu, J., & Torres, V. E. (2025). Vasopressin V1a and V1b receptor antagonism does not affect the efficacy of tolvaptan in Polycystic Kidney Disease. American journal of physiology. Renal physiology, 10.1152/ajprenal.00350.2024. Advance online publication. Https://doi.Org/10.1152/ajprenal.00350.2024

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    Gene Therapy For Inherited Disease In Infants

    As newborn screening and rapid DNA sequencing become routine, we are poised to catch and treat ... More inherited diseases at their earliest stages. Today, we can intervene in the first days or weeks of life. Tomorrow, we will intervene before birth.

    Image by freepik

    For the first time, we are witnessing therapies that can fundamentally alter the course of inherited disease lifelong. The most recent breakthrough describes treating inherited disease in infants. In a case in Nature Medicine, a premature baby with a devastating genetic epilepsy syndrome achieved a 60% reduction in life-threatening seizures following treatment with an experimental therapy.

    This is the first installment in a two-part series describing the opportunities for correcting inherited defects before and immediately after birth. These therapies have provided a chance for those inherited diseases to be treated. Part 1 focuses on the treatment of a newborn. In contrast, Part 2 examines novel applications in the uterus as fetuses before they are born.

    Detecting Inherited Diseases: How Early Can We Know?

    Today, doctors can spot many genetic changes long before they cause problems. Sometimes, this is done through a noninvasive blood test from the mother during pregnancy or from a tiny drop of blood taken from a newborn's heel. These samples are analyzed using powerful genetic sequencing tools to search for signs of hundreds of inherited diseases quickly and accurately.

    With the help of artificial intelligence, doctors can screen for hundreds of conditions rapidly and accurately, making early detection more accessible than ever before. My new book explores how these breakthroughs are changing the lives of children and adults alike. For some families, this early detection is life-changing.

    In a recent case, a newborn began having seizures just days after birth. Using rapid genome sequencing to look for changes in the baby's DNA, they searched for anything that might explain the symptoms. They found a mutation in a gene known to cause a rare form of severe epilepsy.

    The ongoing electrical chaos caused by the mutation impairs brain development. The seizures can also cause delays or regressions in motor skills, language, and social interaction. Additionally, many suffer from sensory issues, losing the ability to track objects visually or respond to sounds. The discovery of the mutated gene allowed them to move quickly to the next step: targeted treatment.

    Targeted Treatment for Inherited Disease in Infants

    More tools than ever before are available to address the root cause when a concerning genetic change is detected. In this case, they used an innovative therapy designed to "quiet" the faulty gene, aiming to reduce the baby's seizures. In the reported case, the preterm infant receiving the therapy saw seizure frequency plummet from 20–25 hourly events to just 5–7.

    Current data showed that the therapy's effects waned after 4–6 weeks due to declining concentrations of the medicine, requiring repeat injections. The therapy proved safe over 20 months, and 19 treatments were performed, with no severe side effects observed. There is also strong clinical evidence of this treatment being effective in multiple animal models, though there are still challenges.

    Challenges Remain in Treating Pediatric Epilepsy

    Finding optimal dosing intervals for preterm infants is particularly challenging, as their rapid growth can significantly affect drug metabolism. Furthermore, frequent dosing risks overwhelming infant systems, while longer intervals may allow seizures to reappear and jeopardize developmental progress. Early trials indicate that monthly infusions might help maintain therapeutic levels.

    Safety is also a top priority as these therapies advance. While early trials have not reported organ toxicity or immune reactions, the long-term effects of chronic treatment with this therapy in developing brains remain uncertain. Prolonged exposure could disrupt key cognitive development processes. Still, the implications are profound.

    The Bigger Picture

    This case is more than a single success—it signals a paradigm shift. As newborn screening and rapid DNA sequencing become routine, we are poised to catch and treat inherited diseases at their earliest stages. Today, we can intervene in the first days or weeks of life. Tomorrow, we will intervene before birth.

    These kinds of breakthroughs are no longer a distant dream. Science and medical research are still pushing the cutting edge. Already, fetal surgeries have corrected structural defects in utero or the womb. The next leap is here: treating inherited disorders at the molecular level before a child is even born. The following story in this series will highlight the first successful use of gene therapy to treat spinal muscular atrophy before birth. The impact is profound for these children and their families. Early intervention can prevent irreversible damage, offering the potential for a normal childhood and a dramatically improved quality of life.

    Looking Forward

    As costs fall and technology improves, all newborns could soon have their DNA sequenced, enabling targeted treatments at the earliest and most effective stage. Over time, this approach will expand access, reduce the burden of inherited disease, and reshape the future of human health care.

    One profound question remains: If we correct a genetic error in a child, will that change be passed on to future generations? For now, most therapies target the body's somatic cells, not the germline—but as our tools improve, the possibility of heritable cures edges closer, raising hope and new ethical questions.

    As we stand at the frontier of precision neurology, cases like this illuminate a path forward. For families facing rare genetic epilepsies, this medicine offers more than seizure control. They provide a lifeline to cognitive and developmental gains previously deemed unattainable. While larger trials are needed, the era of disease-modifying therapies for pediatric brain disorders has unequivocally begun. Part 2 will delve into how correcting genetic errors before birth could rewrite the trajectory of inherited diseases.






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