SAN FRANCISCO—Scientists at Gladstone Institutes have flipped the traditional approach to finding potential treatments for deadly diseases. Instead of starting with a disease and hunting for a cure, they began with vitamins and systematically identified genetic diseases that could benefit from high-dose supplements.

Using this framework, the team discovered that vitamin B3 supplementation, when tested in mice, can successfully treat a devastating genetic disease known as NAXD deficiency. Children with this disease typically die within their first few months of life. But in a new mouse model of the condition, vitamin B3 therapy extended lifespan more than 40-fold and eliminated symptoms of the disease.

The study also identified dozens of other genetic conditions that may respond to vitamin B2 or B3 therapy, potentially opening new treatment avenues for rare diseases using safe, inexpensive treatments.

“Our goal is to revisit classical vitamin biology with causal and rigorous frameworks,” says Gladstone Investigator Isha Jain, PhD, senior author of the new study published in Cell. “Rather than randomly supplementing vitamins, we’re using modern genetics to systematically identify which diseases can be treated with which vitamin.”

Reviving Vitamin Research

In the early 1900s, scientists discovered that diseases like scurvy and beriberi could be cured by specific vitamins, work that earned multiple Nobel Prizes. In more recent years, however, cheap and easily available supplements have led to indiscriminate use, with people often taking vitamins without specific health evidence.

Jain, who is also a core investigator at Arc Institute and an associate professor at UC San Francisco, believes there’s vast untapped potential for new targeted vitamin therapies. In October, she won a prestigious NIH Transformative Research Award to fuel her work reviving the field of vitamin biology with modern science.

Her lab has developed an approach to systematically identify diseases that could be treated with individual vitamins. The researchers removed specific genes from human cells using CRISPR gene editing technology, and then tested whether cells survived better when exposed to high levels of vitamins.

“Each cell represented a different genetic condition that can affect humans,” says Skyler Blume, a research associate in Jain’s lab and co-first author of the new paper. “We asked: if we have a vitamin as a potential therapy, which of these genetic conditions could it treat?”

When they carried out the screen using vitamin B3, they discovered that cells lacking NAXD survived far better in the high-vitamin conditions. In children, mutations in the NAXD gene lead to severe developmental delays and death.

“Our screen suggested that something as simple as giving vitamin B3 could make a difference for human patients,” says co-first author Ankur Garg, PhD, a postdoctoral fellow in Jain’s lab.

There was existing evidence, particularly in yeast, that healthy NAXD repairs damaged versions of NADH, an energy-carrying molecule that cells use as fuel. When NAXD is mutated and not functioning, damaged NADH builds up in the brain, while depleting the active version. This causes a cascade of problems.

A Potential Path for Treating NAXD

To test whether vitamin B3 would make a difference in NAXD deficiency across the body—not just in isolated cells—the team generated the first mouse model of NAXD disease. The animals looked normal at birth, but rapidly deteriorated and died within days. The researchers showed that the damaged form of NADH had accumulated throughout their bodies and that the brain and skin were also highly deprived of the normal, active form of NADH, as well as another vital molecule known as serine.

When Jain’s group gave the mice daily injections of high-dose vitamin B3 starting immediately after birth, the results were striking.

“The treated mice were indistinguishable from their healthy littermates,” Blume says.

While untreated mice died around five days old, the treated mice were still alive at 300 days—at which point the experiment was halted. Brain inflammation disappeared, and NADH and serine levels normalized.

The findings offer hope for children with NAXD deficiency, the team says. Several case reports have described patients who improved after receiving supplements, but the evidence had been only anecdotal. The new study provides experimental evidence that vitamin B3 therapy can address the root cause of the disease. And the fact that treatment must begin at birth underscores the importance of early diagnosis.

“This tells us that NAXD should be added to newborn screening panels,” Jain says. “If we can diagnose children immediately after birth and start therapy, we may be able to save lives.”

Beyond NAXD, the framework developed in Jain’s lab identified dozens of other disease genes potentially responsive to vitamin therapy. She and her team plan to screen other vitamins for their potential to treat genetic diseases, as well as follow up on other cell types that showed improved growth in high-vitamin-B conditions.

“This framework is completely scalable,” Jain says. “We could potentially identify vitamin therapies for hundreds of genetic diseases. We hope other labs will also apply this framework to other micronutrients, beyond vitamins”

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About the Study

The paper, “Vitamin B2 and B3 Nutrigenomics Reveals a Therapy for NAXD Disease,” was published in the journal Cell on February 25, 2026. The authors are Ankur Gard, Skyler Blume, Helen Huynh, Alec M. Barrios, Onurkan O. Karabulut, Ayush M. Midha, Adam Turner, B. Vittorio Resnick, Xuewen Chen, Ayushi Agrawal, Mina Negahban, Sophia C. K. Nelson, Andrew C. Yang, Michela Traglia, Reuben Thomas, Ryan Corces, and Isha Jain of Gladstone Institutes; Qian Zhao and Hening Lin of Cornell University and The University of Chicago; Jaeyeon Kim and Mercedes Paredes of UC San Francisco; Liuji Chen and Qitao Ran of University of Texas Health Science Center; and Alison M. Ryan, Reece C. Larson, Ramon Sun of University of Florida.

The work was supported by a gift from Renee and David Wentz, the National Institutes of Health (DP5OD026398, C06 RR018928), the Searle Scholars Program, Arc Institute, and the American Heart Association.

About Gladstone Institutes

Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.

Journal

Cell

Funder

Renee and David Wentz,
National Institutes of Health,
Searle Scholars Program,
Arc Institute,
American Heart Association

DOI

10.1016/j.cell.2026.01.022

Recent groundbreaking research from Gladstone Institutes and UCSF has unraveled the intricate regulatory landscape that fine-tunes FOXP3 expression in immune cells. Published in the journal Immunity, this study offers unprecedented insights into how genetic switches govern the precise levels of FOXP3, thus controlling immune function with remarkable specificity. The findings not only elucidate why FOXP3 behaves differently in human versus mouse immune cells but also pave the way for innovative immune therapies targeting autoimmunity and cancer.

At the heart of this exploration lies the question: how is FOXP3 expression meticulously controlled? Regulatory T cells (Tregs), which act as immune brakes to prevent autoimmunity, rely on this gene to function correctly. Without FOXP3, Tregs fail, leading to unchecked immune reactions and severe autoimmune disorders in humans. Curiously, unlike mouse Tregs that express FOXP3 exclusively, human conventional T cells—typically pro-inflammatory—can transiently switch on FOXP3, a phenomenon that has long mystified immunologists.

To dissect this complexity, the research team employed expansive CRISPR gene-editing screens to examine 15,000 DNA regions flanking the FOXP3 gene. These regions contain cis-regulatory elements, akin to molecular dimmer switches, that adjust gene activity. Through systematic disruption of these sites in both mouse and human T cells, researchers composed the first functional map of the FOXP3 regulatory circuitry, revealing distinct dimmer switches in different immune cell types.

Crucially, the study revealed that in human regulatory T cells, multiple redundant enhancers collectively maintain sustained FOXP3 expression. This redundancy ensures resilience; removing any single enhancer results in only minor expression changes, highlighting a robust safeguard mechanism. By contrast, conventional T cells possess a more streamlined regulatory architecture, involving just two enhancers and a surprising inhibitory element—a genetic repressor—that acts as a molecular brake on FOXP3 activation.

This sophisticated regulatory circuit, described by first author Dr. Jenny Umhoefer, underscores a delicate interplay between ‘gas pedals’ (enhancers) and ‘brakes’ (repressors) that together orchestrate precise FOXP3 expression. To uncover what proteins orchestrate these switches, the scientists conducted a complementary genome-wide CRISPR screen targeting nearly 1,350 transcription factors and regulatory proteins. This approach identified key players that bind directly to FOXP3 enhancers and repressors, further refining the architecture of this gene regulatory network.

Utilizing ChIP-seq and other advanced genomic technologies, the team mapped protein-DNA interactions across the FOXP3 locus, linking regulatory proteins to specific enhancers and repressor elements. This integrative methodology enabled a comprehensive understanding of the molecular machinery that regulates FOXP3, transcending previous studies limited to isolated genomic elements. According to co-author Dr. Ansuman Satpathy, this represents an extraordinary step forward in connecting local DNA features to the transcriptional proteins governing gene expression.

One of the study’s most striking revelations was the resolution of the species-specific behavior of FOXP3 in conventional T cells. The researchers initially hypothesized that humans possess unique enhancers absent in mice, accounting for FOXP3 activation in human conventional T cells. Unexpectedly, mouse conventional T cells share the same enhancers, but differ in the presence of a robust repressor element that shuts off FOXP3. Disabling this repressor in mice unleashed FOXP3 expression in conventional T cells, effectively mimicking the human regulatory pattern.

This finding not only unravels the species divergence enigma but also offers profound evolutionary insights into how gene regulatory circuits adapt across organisms. It emphasizes the critical role of repressive elements, which have been largely overlooked compared to enhancers, in dictating gene expression patterns fundamental to immune cell identity and function.

Beyond basic science, these discoveries have exciting translational potential. A detailed map of FOXP3’s regulatory elements equips researchers with targets to finely manipulate regulatory T cell activity for therapeutic purposes. Enhancing FOXP3 expression could bolster regulatory T cells, offering relief in autoimmune diseases by tempering harmful inflammation. Conversely, dampening FOXP3 might unlock immune responses against tumors, empowering cancer immunotherapies by unleashing the full anti-cancer potential of T cells.

Dr. Alex Marson, who led the study, highlights how these newfound insights could accelerate precision cell engineering strategies. By distinguishing cell-type-specific gene control mechanisms, scientists can develop more targeted interventions that modulate immune responses with minimal off-target effects. This represents a paradigmatic shift towards rational therapies addressing immune-related diseases’ complexity with unprecedented specificity.

This research stands at the confluence of genomic technology and immunology, leveraging CRISPR’s immense power to probe gene regulation at an unprecedented scale and resolution. It exemplifies how functional genomics can unravel biological mysteries while informing therapeutic innovation, heralding a new era of molecular immune circuit engineering.

The work also reflects a collaborative triumph among leading institutions, including Gladstone Institutes, UCSF, Stanford, UC Berkeley, and ETH Zürich, supported by numerous prestigious funding agencies and foundations. As research continues, the comprehensive understanding of FOXP3 regulation is poised to drive breakthroughs in treating a spectrum of diseases rooted in immune dysregulation.

In summary, this landmark study illuminates the complex regulatory network controlling FOXP3 expression, revealing intricate enhancer and repressor dynamics that fine-tune immune function across species. It resolves a long-standing biological puzzle and opens exciting avenues for designing next-generation immunotherapies. Armed with these insights, the scientific community moves closer to precisely modulating the immune system’s brakes and accelerators to combat autoimmunity and cancer with sophistication and precision.

Subject of Research: Regulation of FOXP3 gene expression in immune cells and its implications for immune system balance, autoimmunity, and cancer.

Article Title: FOXP3 expression depends on cell-type-specific cis-regulatory elements and transcription factor circuitry

News Publication Date: November 13, 2025

Web References:

• DOI link
• Nobel Prize Summary 2025
• Gladstone Institutes

Image Credits: Michael Short/Gladstone Institutes

Keywords: Immune cells, T lymphocytes, Gene regulation, Transcription factors, CRISPRs, Epigenetics, Regulatory T cells, Autoimmunity, Autoimmune disorders, Cancer

Nearly 50% of babies born with Down syndrome, also referred to as trisomy 21, are affected by significant heart defects. These congenital malformations often necessitate surgical intervention during the initial months following birth. Previous research indicated that the causative factor stemmed from an additional copy of chromosome 21, the hallmark of Down syndrome. However, pinpointing the specific gene responsible for the heart anomalies remained elusive. The innovative approach taken by the Gladstone team combines advanced stem cell technology and artificial intelligence, leading them to the identification of HMGN1 as a significant contributor to these heart defects.

Historically, the challenge in identifying the gene behind congenital heart defects in Down syndrome rested in the complexity of the human genome. With numerous genes present on chromosome 21, it was challenging to determine which specifically was responsible for the cardiac issues observed. Scientists traditionally relied on cell samples from separate individuals, creating uncertainty due to inherent genetic variations. However, by focusing on individuals with mosaic Down syndrome—who possess a mix of cells with differing chromosome copies—the team was able to eliminate such uncertainties and establish a clearer pathway for investigation.

Leveraging induced pluripotent stem (iPS) cell technology, the researchers derived heart cells from mosaic individuals, allowing them to observe how the additional genetic material affected these cells’ development. This unprecedented methodology provided a unique opportunity to directly contrast cells that either possessed two or three copies of chromosome 21. Notably, the analysis revealed significant differences in the morphology and function of the heart cells, sparking curiosity regarding the gene responsible for this shift.

As they delved deeper, the researchers employed a CRISPR-based technology to activate each of the candidate genes found on chromosome 21, observing their effects on normal heart cells. This meticulous process yielded a plethora of data that required sophisticated analysis. To decode this information, the team collaborated with experts in artificial intelligence, who developed algorithms to interpret the results effectively. This collaboration unveiled HMGN1 as the gene that, when overexpressed, caused heart cells to mimic the abnormal characteristics associated with Down syndrome.

The identification of HMGN1 not only solves an age-old mystery, but it also opens up potential avenues for therapeutic intervention. Subsequent studies involving animal models demonstrated that when the levels of HMGN1 were reduced, the typical heart defects correlated with Down syndrome were effectively eliminated. This discovery validates the researchers’ hypothesis that the presence of three copies of HMGN1 is responsible for the cardiac anomalies experienced by these individuals.

Beyond HMGN1, scientists are beginning to explore the possibility that other genes also contribute to the cardiac malformations associated with Down syndrome. Early indicators suggest that genes such as DYRK1 may play a role alongside HMGN1, highlighting the complexity of genetic interactions that lead to congenital heart disease. As research progresses, it will be crucial to delineate the interplay between these genes, especially in the context of developing targeted therapies that could mitigate complications faced by patients.

This new understanding of the genetic basis for heart defects in Down syndrome also bodes well for future research into other genetic disorders characterized by chromosomal abnormalities. The Gladstone team’s findings provide a critical framework for examining how alterations in chromosomal number can influence disease pathology, which could translate into groundbreaking insights for various genetic and developmental disorders.

The implications of this research extend beyond merely treating heart defects. As scientists continue to refine techniques for controlling the expression of genes involved in congenital heart disease, there exists the potential to develop preventive strategies, possibly even during the prenatal stage. This could fundamentally alter the landscape of how congenital disabilities are approached, providing new hope for families affected by Down syndrome.

To summarize, the discovery of HMGN1 restructuring the landscape of congenital heart defects in Down syndrome emphasizes the potential of integrating cutting-edge genomic technologies with advanced computational methods. The collaborative efforts between researchers at Gladstone, stem cell science, and artificial intelligence illustrate the future of medicine rests on interdisciplinary cooperation, pushing the boundaries of what we understand about genetic disorders.

Thanking the Gladstone Institutes for their visionary exploration and groundbreaking research, we now stand on the precipice of potentially life-altering therapies, underscoring the importance of continued investment in scientific research. This monumental step forward represents not just a significant scientific achievement but also a ray of hope for individuals living with Down syndrome and their families.

With emerging results like these, the future may hold considerable promise for genetically targeted therapies that could revolutionize treatment protocols and improve the quality of life for those affected by congenital heart disease related to chromosomal disorders.

As we move forward, the continued exploration into the genetic foundations of various health conditions remains critical. Advancements in this field of study will undoubtedly usher in a new era of precision medicine, paving the way for more profound insights into not only Down syndrome but a plethora of genetic disorders. The ongoing commitment to decoding the complexity of the human genome is a necessity for building a healthier future for generations to come.

Subject of Research: HMGN1 in Congenital Heart Defects Related to Down Syndrome
Article Title: Myocardial reprogramming by HMGN1 underlies heart defects in trisomy 21
News Publication Date: October 22, 2025
Web References: Gladstone Institutes
References: Nature DOI: 10.1038/s41586-025-09593-9
Image Credits: Gladstone Institutes

Keywords

Down syndrome | Genetics | Stem cell research | Artificial intelligence | Drug development | Cardiology | Congenital heart disease

At the forefront of this scientific renaissance is Dr. Isha Jain, a researcher at the Gladstone Institutes in San Francisco, who has embarked on an ambitious journey to reinvigorate vitamin biology through cutting-edge research methodologies. Recently, Dr. Jain was awarded the National Institutes of Health (NIH) 2025 Transformative Research Award, a prestigious grant totaling $6.6 million that supports high-risk, high-reward science seeking to redefine existing biomedical paradigms. This endorsement not only acknowledges the potential of her work but underscores the urgency of modernizing vitamin research.

Vitamin biology has historically been underexplored given the complexity of the metabolic networks vitamins engage with. These micronutrients serve as cofactors, substrates, and regulators in numerous enzymatic processes vital to cellular function. Dr. Jain posits that a systemic and comprehensive mapping of vitamin-dependent enzymes and pathways will unlock new avenues for precise therapeutic interventions. This high-resolution understanding will elucidate which diseases are amenable to vitamin modulation and how these molecules influence pathophysiological mechanisms.

Her past research has already illuminated significant biochemical insights, particularly regarding oxygen homeostasis. Dr. Jain’s laboratory characterized how hyperoxia, or excessive oxygen exposure, leads to cellular and tissue damage, a phenomenon that exacerbates conditions such as mitochondrial dysfunction. Building upon these discoveries, her recent development of a pharmacological agent mimicking the benefits of high-altitude, low-oxygen environments shows promise for treating mitochondrial diseases like Leigh syndrome, where oxygen imbalances are detrimental.

This intersection of oxygen biology and metabolism naturally extends to vitamin function, as many vitamins act as essential cofactors in redox reactions and mitochondrial energy production. Dr. Jain’s strategy involves leveraging modern techniques, including mass spectrometry-based metabolomics, CRISPR gene editing, and systems biology approaches, to comprehensively profile vitamin interactions at molecular, cellular, and organismal levels. Her research aims to reintegrate vitamins into the scientific narrative not as mere supplements but as pivotal bioactive agents with therapeutic potential.

The potential implications of this work are profound. By redefining vitamin biology, Dr. Jain envisions a future where personalized vitamin-based therapies become a reality. Such treatments would tailor vitamin administration to individual metabolic profiles and genetic backgrounds, thereby optimizing therapeutic outcomes while minimizing adverse effects. This paradigm shift could particularly benefit patients with genetic disorders and metabolic syndromes that currently lack effective treatments.

Despite the foundational discoveries in the early 20th century that identified many essential vitamins, the field has experienced a prolonged scientific neglect. Modern biomedical science now possesses the tools to revisit these foundational questions with unprecedented precision. Dr. Jain emphasizes that the integration of systems biology and advanced analytical methods will transform vitamin biology from a descriptive to a predictive science, enabling targeted intervention strategies.

Her visionary work also highlights the broader challenges within nutritional science. Vitamins are often consumed with limited understanding of their molecular targets or physiological impacts, leading to inconsistent or suboptimal use. The rigorous elucidation of vitamin-dependent metabolic pathways will not only foster clinical innovations but also refine public health guidelines and nutritional recommendations based on solid mechanistic insights.

Dr. Benoit Bruneau, director of the Gladstone Institute of Cardiovascular Disease, lauds Dr. Jain’s efforts as quintessential “high-risk, high-reward” research. He underscores that bold investigative approaches in neglected fields such as vitamin biology frequently yield groundbreaking discoveries that ripple through multiple domains of health science. The potential to fundamentally reconceive nutritional therapies stands to transform clinical approaches to a wide spectrum of diseases.

The pioneering spirit and methodological rigor of Dr. Jain’s research epitomize Gladstone Institutes’ commitment to disruptive innovation in biomedical research. Founded in 1979 and situated in San Francisco’s Mission Bay neighborhood—an epicenter for scientific and technological innovation—Gladstone provides an incubator where visionary scientists can challenge existing dogmas and pursue big ideas with transformative potential.

Dr. Jain’s project symbolizes an essential pivot in biomedical research, reminding the scientific community that sometimes revisiting long-established knowledge through modern technology can unveil entirely new therapeutic landscapes. As the project progresses, the global health community watches keenly, anticipating breakthroughs that could finally unlock the extensive yet underutilized therapeutic power of vitamins.

The NIH Transformative Research Award backing Dr. Jain exemplifies the need to foster innovative, high-impact research capable of reshaping foundational biological concepts. This funding enables her lab to deploy an integrated suite of technologies—ranging from single-cell sequencing to computational modeling—aimed at decoding the multidimensional interactions of vitamins within biological systems, and translating these findings into clinical advancements.

As vitamin biology advances into this new era, the scientific and medical communities will benefit from a richer, more nuanced understanding of how these essential micronutrients contribute to health and disease. Ultimately, Dr. Jain’s work promises to inaugurate an era where vitamins transcend their conventional status, taking their rightful place at the center of personalized medicine.

Subject of Research: Revitalization of Vitamin Biology Using Modern Scientific Techniques and Systems Biology Approaches to Understand Vitamin-Dependent Metabolic Pathways and Develop Personalized Vitamin-Based Therapies.

Article Title: Transforming Vitamin Biology: Modern Science Illuminates the Therapeutic Potential of Vitamins

News Publication Date: Not explicitly stated in the provided content.

Web References:

• Gladstone Institutes Profile of Isha Jain, PhD: https://gladstone.org/people/isha-jain
• NIH Transformative Research Award Overview: https://commonfund.nih.gov/tra/award-overview
• Research on Oxygen-Induced Tissue Damage: https://gladstone.org/news/researchers-discover-how-too-much-oxygen-damages-cells-and-tissues
• Development of Low-Oxygen Mimetic Drug: https://gladstone.org/news/daily-drug-captures-health-benefits-high-altitude-low-oxygen-living
• Gladstone Institutes Homepage: https://gladstone.org/

Image Credits: Gladstone Institutes

Keywords: Vitamins, Metabolism, Drug Development