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Approaches to Reducing Toxicity and Side Effects in Cell and Gene Therapy

Cell and gene therapy encompasses a broad range of therapeutic interventions for diseases that have proved refractory to treatment with conventional pharmaceutical approaches. Perhaps the most familiar FDA-approved modality in the cell and gene therapy field is chimeric antigen receptor (CAR) T-cell therapy, which involves genetic modification of a patient’s own T cells to identify and eliminate malignant cell lineages in acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma.

Although only 20 or so cell or gene therapies have been FDA-approved, the area holds considerable promise for investment. The global market was valued at nearly $9 billion in 2025, and growth has been projected at over 15% per year from 2026 to 2035. As with any pharmaceutical product, however, the potential of cell and gene therapy relies in large part upon minimizing risks to patient health from adverse effects. Numerous companies, from both prominent names in the field to smaller startups, are developing solutions to mitigate the deleterious consequences of cell and gene therapy.

Reducing cytokine release syndrome

Cytokines are a broad family of small proteins and peptides that cell lineages of the innate and adaptive immune systems employ to communicate with each other and coordinate timely and appropriately scaled responses to foreign antigen-containing cells. Cytokine release syndrome (CRS) occurs when hyperactivation of one or more immune lineages results in the release of excessive quantities of cytokines into the circulation.

“As a scientific community, we’ve been researching CAR T-cell therapy for over 30 years and have grown together in our understanding of the body’s immune response to treatment, from both a safety and efficacy perspective,” says Rosanna Ricafort, MD, vice president and global program lead of hematology and cell therapy at Bristol Myers Squibb. “We have evolved our ability to characterize, stage, and manage potential side effects, allowing for timely and thoughtful interventions of the most commonly associated side effects like CRS.”

Ricafort cited clinical data presented at the 2025 American Society for Clinical Oncology (ASCO) meeting in Chicago demonstrating that over 95% of instances of CRS and other adverse events arising from BMS’s CD19-directed CAR T-cell therapy (BreyanziR) occurred in the first two weeks after onset of therapy. “These and other studies have helped establish the largely predictable safety profile of CAR T-cell therapy to date,” Ricafort pointed out.

Minimizing side effects

The NF-κB and prostaglandin E2 pathways are prominent regulators of the activation and differentiation of pro-inflammatory T cell lineages. Excessive signaling through these pathways results in cytokine amplification, which contributes to CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of some types of CAR T-cell therapy.

CytoAgents, a clinical-stage biotech company, is developing CTO1681, an orally administered prostaglandin signaling inhibitor that has been shown to offset CRS and ICANS toxicities associated with CAR T-cell therapy of lymphoma patients. At the 2025 European Society for Medical Oncology (ESMO) Immuno-Oncology Congress in London, CytoAgents presented non-clinical data showing that CTO1681 treatment reduced secretion of TNF-α, IL6, and other key CRS-associated cytokines with no impairment of CAR T-cell mediated cytotoxicity on lymphoma cells.

“These data suggest CTO1681 could enable safer CAR T-cell therapy administration, support outpatient treatment paradigms, and broaden patient access without compromising anti-tumor efficacy,” said Teresa Whalen, CEO at CytoAgents. CTO1681 is currently in Phase Ib/IIa trials for cancer patients undergoing CAR T-cell therapy, with potential expansion into additional therapeutic spaces including asthma and chronic obstructive pulmonary disease.

Adding immunosuppressants

A potential side effect of adeno-associated virus (AAV)-based gene transfer approaches is acute liver injury resulting in part from CRS in patients receiving AAV therapy. Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder caused by mutations or changes in the DMD gene, resulting in reduced levels of the protein dystrophin.

Adeno-associated virus
Credit: Kateryna Con / Getty Images / Science Photo Library

Elevidys, developed by Sarepta Therapeutics, is an AAV-based therapy approved for the treatment of DMD that stimulates targeted production of a truncated form of dystrophin in skeletal muscle. “Individuals with non-ambulatory Duchenne face profound unmet need and fewer treatment options,” says Louise Rodino-Klapac, PhD, president of R&D and development and technical operations at Sarepta. Topline data released earlier this year showed that Elevidys treatment resulted in significant improvement in key clinical ambulatory metrics in patients.

As part of its ENDEAVOR clinical trial, Sarepta Therapeutics is evaluating the potential of supplementing Elevidys with sirolimus to reduce potential acute liver injury (ALI) complications. Sirolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor that suppresses responses of T and B cells to interleukin 2, which functions to stimulate proliferation of helper, cytotoxic, and regulatory T cells.

Developing non-integrating therapies

As an alternative approach to supplementing cell and gene therapy modalities with existing immunosuppressants, other companies are modifying CAR T-cell therapy to reduce the risk of CRS and other side effects. Myasthenia gravis, a chronic fatigue-inducing autoimmune disorder in which signals between nerves and muscles are compromised, results in part from the secretion of autoantibodies from B-cell maturation antigen (BCMA)-expressing B plasma cells.

Conventional BCMA-directed CAR T-cell approaches rely on the integration of lentiviral or gamma-retroviral vectors to encode the CAR and typically involve lymphodepletion chemotherapy that can be accompanied by acute and delayed toxicity. In contrast, non-integrating (i.e., mRNA-based) BCMA-directed CAR T-cell therapies may circumvent this toxicity due to the lack of requirement for chemotherapy.

Cartesian Therapeutics is developing an mRNA-based BCMA-targeted CAR T-cell therapy for myasthenia gravis, Descartes-08. At the 2025 American Academy of Neurology (AAN) Annual Meeting in San Diego, results were reported of a Phase IIb clinical trial of Descartes-08 in myasthenia gravis. In the trial, adverse event rates were similar between groups receiving Descartes-08 and the placebo group, and were predominantly mild to moderate in nature, with no cases of CRS or ICANS reported.

“The impressive strength and duration of response shown in the data reinforce our confidence in the potential of Descartes-08 to transform the current treatment landscape in MG, offering patients a safe, flexible, and durable treatment option,” said Carsten Brunn, PhD, president and CEO of Cartesian.

Engineering chimeric receptors

Modifications of CAR T-cell therapy to improve clinical efficacy and reduce side effects can also encompass modification of the molecular structure of the chimeric receptor itself. D domains are highly selective targeting domains incorporated into newer generations of CARs that enhance targeting of pathological cell types and reduce immunogenic responses in patients that give rise to unwanted side effects.

One example of such next-generation CAR T-cell therapies, anito-cell, has been co-developed by Arcellx, Kite Pharma, and Gilead. Anito-cel is an autologous anti-BCMA CAR T-cell therapy for the treatment of relapsed/refractory multiple myeloma patients.

Phase II trial results in multiple myeloma presented at the 2025 American Society of Hematology (ASH) meeting in Orlando showed an overall response rate of 97% and a complete response rate of 68%. Importantly, in the context of side effects, there were no delayed neurological symptoms, and for most patients, only low-grade CRS was observed, which was resolved within a few days.

“The anito-cel D-domain BCMA binder could be important to our work in in vivo cell therapy, further strengthening our potential in oncology and inflammation,” said Daniel O’Day, chairman and CEO of Gilead. “Anito-cel could become a foundational treatment for multiple myeloma over time, including earlier lines of therapy.”

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The State of Precision Medicine

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Panelists:

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Becky Quick

Anchor
CNBC’s Squawk Box

Panelist

Image of Becky Quick

Becky Quick

Becky Quick is an anchor of CNBC’s popular morning show, Squawk Box, and an award-winning journalist and broadcaster. More importantly, she is the mother of a child with the rare genetic disease, SYNGAP1. The disease, which affects about 1,700 people globally, is derived from a mutation in the SynGAP protein, which is required for brain development. Becky’s daughter Kaylie was diagnosed at three years old, which opened doors to form connections with other families in the rare disease space who are facing similar situations. Becky was the driving force behind the formation of CNBC Cures, hosting and moderating the inaugural summit in New York City in March 2026. The summit featured numerous experts and commentators in rare disease therapeutics and personalized medicine sharing ideas to expedite funding and research for rare genetic disorders.

Becky holds a degree in political science from Rutgers University. Prior to her role as a CNBC anchor, she was a columnist at Fortune and a reporter at the Wall Street Journal.
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Anne Wojcicki

CEO
23andMe Research Institute

Panelist

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Anne Wojcicki

Anne Wojcicki is the founder and CEO of 23andMe and the TTAM Research Institute. She is committed to putting individuals at the center of their health information and decisions with choice and transparency, and in turn empowering them to participate in research. Anne co-founded 23andMe in 2006, three years after the first human genome was sequenced. Her goal was to help people access, understand, and benefit from the human genome and fundamentally change healthcare in the process. Although the company filed for bankruptcy in 2025, Anne maintained her interest in steering the company forward. She formed the TTAM Research Institute, a nonprofit medical research organization, to acquire the company for $305 million.

Prior to founding 23andMe, Anne spent a decade on Wall Street investing in healthcare and felt frustrated by a system built around monetizing illness instead of incentivizing prevention. Anne’s vision and persistence powered an industry-first community approach to genetic research. This novel, web-based research model has resulted in thousands of new genetic discoveries and brought personalized medicine to millions of people.
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Brian Bigger, PhD

Chair, Advanced Therapeutics
University of Edinburgh, U.K.

Panelist

Image of Brian Bigger, PhD

Brian Bigger, PhD

Brian Bigger, PhD, is the chair of advanced therapeutics at the Institute of Regeneration and Repair at the University of Edinburgh. His group develops innovative gene and cell therapies, especially neurological lysosomal diseases like Hunter syndrome, and brings these treatments to patients. In particular, the focus is on making novel stem cell gene therapies available to patients with neurological diseases and dementias. Brian’s lab has developed three hematopoietic stem cell gene therapies for mucopolysaccharidosis types II and III (MPS II and MPS III). The first therapy developed in the lab (substrate reduction therapy for MPSIII) entered a Phase III clinical trial in mid 2014.

Brian earned his PhD in gene therapy from Imperial College London. After four years developing a stem cell gene therapy approach for hemophilia B at Cancer Research UK, Brian worked on hematopoietic stem cell migration at the National Blood Service and Oxford University.
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Carrie Haverty

Vice President of Medical Affairs & Clinical Strategy
Mirvie

Panelist

Image of Carrie Haverty

Carrie Haverty

Carrie Haverty is vice president of medical affairs and clinical strategy at Mirvie, leading efforts to develop the Mirvie RNA platform using a simple blood test to reveal a pregnancy’s unique biology and predict complications months before they occur. Carrie is also the 2026 president of the National Society of Genetic Counselors, having previously served on the board of directors as chair of the membership committee and various other volunteer roles since she was in graduate school.

Carrie earned her graduate degree in genetic counseling from the University of California, Irvine, and she is a Certified Genetic Counselor. She started her career working in high-risk prenatal care and focused on providing broad access to new diagnostic technologies. Her clinical experience served as the foundation for leading cutting-edge product development and commercialization of new technologies at Counsyl, Myriad Genetics, and Miroculus, prior to joining Mirvie.

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Welcome to the 2026 State of Precision Medicine virtual summit, hosted by Inside Precision Medicine. This year’s summit focuses on the existing gaps in precision medicine as we ask: How do we make treatment equitable and accessible for all patients across the disease continuum?

On June 3rd, the editors of Inside Precision Medicine will feature an outstanding line-up of guests highlighting the challenges and urgency of expanding access to disease therapies and empowering patients and consumers.

Agenda Highlights:

  • Becky Quick, co-anchor of CNBC’s Squawk Box and the founder of CNBC Cures, discusses her own family’s rare disease journey and her prescription to expand access to rare disease therapeutics 

  • Anne Wojcicki, CEO of the 23andMe Research Institute, speaks on the consumer genetics pioneer’s recent renaissance leading the newly re-imagined organization

  • Brian Bigger, PhD, and Rob Wynn, MD, scientists and clinicians at Manchester University, share insights from their work on stem cell gene therapy and its potential to offer hope for patients with rare diseases such as Hunter syndrome. They are joined by Ricky Chu, father of two children with Hunter syndrome, a rare neurodevelopmental disorder 

  • Carrie Haverty, president of the National Society of Genetic Counselors, hosts a panel on the current trends and challenges in genetic counseling 

  • Saralyn Mark, MD, first senior medical advisor to both the Office on Women’s Health within the HHS and NASA, boldly explores lessons in women’s health with her guests Dorit Donoviel, PhD, and Kim Templeton, MD

  • Breakout sessions from the summit sponsors, including 10x Genomics and Illumina 

Registration is entirely free. We look forward to seeing you on June 3.

Produced with support from:

10x Genomics logo

illumina logo

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Bioprocessing Applications Laboratory Opened in Korea by Ecolab Life Sciences

Officials at Ecolab Life Sciences report that the company is expanding its bioprocessing business with the launch of a new bioprocessing applications lab (BPAL) in Dongtan, Korea. They say the goal is to provide biopharmaceutical manufacturers across Asia with better local access to downstream process development support.

The site is Ecolab’s first bioprocessing facility in Asia and joins an established applications network in the U.S. and U.K.

BPAL Korea supports process development from early-stage resin screening through studies designed to replicate commercial manufacturing conditions, according to Jenny Tan, vice president and general manager, Ecolab Life Sciences APAC and India. On-site scientists work alongside customers across Asia to help optimize chromatography steps, improve yield and productivity, and accelerate regulatory pathways, with the aim of reducing the need to ship resins and reference materials overseas for development work, she continues.

Asia has become one of the world’s most active biopharmaceutical manufacturing regions, with Korea, China, Japan, India, and Singapore all home to growing pipelines in biosimilars and monoclonal antibody processes that scalable downstream purification. With local technical support now in place, manufacturers across the region can shorten development cycles and maintain consistency with global operations while working to tight regulatory and cost targets, continues Tan.

“Biopharmaceutical manufacturers across Asia are under increasing pressure to scale with speed while meeting demanding regulatory and performance expectations,” she explains. “BPAL Korea strengthens our ability to work side by side with customers, bringing local expertise together with Ecolab’s global, integrated bioprocessing network.”

By combining local scientific support with Ecolab’s innovative Purolite™ resin portfolio, Ecolab’s new BPAL was created to help enable manufacturers to address process challenges earlier, reduce development risk, and advance programs with greater confidence as they prepare for scaleup, says Tan.

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STAT+: New obesity tool aims to predict risk of 18 serious complications

Body mass index has its limitations, but for now it’s the metric medicine often defaults to when predicting weight-related health problems. A new tool promises to better define who’s at risk for obesity complications, based on measures that include BMI but also family history, diet, current illness, and socioeconomic factors culled from medical records.

One aim of the research is to better understand who’s a candidate for an obesity drug, often prescribed based on BMI alone or BMI in combination with another disease. Over time, GLP-1 medications, whose initial target was type 2 diabetes, have revealed their power to ease cardiovascular disease, kidney disease, liver disease, sleep apnea, and osteoarthritis, in addition to promoting significant weight loss. But discerning who’s the best fit for the costly, lifelong treatment has been uncertain. 

“We really wanted to have an integrated model that enables us to look at not one, but 18 different obesity-relevant complications,” Claudia Langenberg, co-author of a study about the new model published Thursday in Nature Medicine, said in a media briefing Tuesday. She is director and professor of medicine and population health at Precision Healthcare University Research Institute of Queen Mary University of London.

Continue to STAT+ to read the full story…

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Bowel and Ovarian Cancer Cases Rise Among U.K. Young Adults

Cases of bowel and ovarian cancer are rising, but only among people under 50, according to research published in the British Medical Journal Oncology today, April 28, 2026. While other types of cancer are also rising in older adults, this particular trend among younger adults is striking. 

A key factor, the researchers’ work suggests, is excess weight. But that does not fully explain the trends they saw.

In particular, there was a significant rise in 11 cancers among the younger adults with known behavioral risk factors. These cancers were: thyroid, multiple myeloma, liver, kidney, gallbladder, bowel, pancreatic, womb lining (endometrial), mouth, breast, and ovarian cancers. 

Rates of all these cancers also rose significantly among the older adults, with the notable exceptions of bowel and ovarian cancers.  

Besides mouth cancer, all 11 cancers associated with known behavioral risks were linked to obesity. And six (liver, bowel, mouth, pancreas, kidney, and ovary) were also linked to smoking; four (liver, bowel, mouth, and breast) were associated with alcohol intake; three (bowel, breast, and endometrial) were linked to physical inactivity; and one (bowel) was associated with dietary factors.

“Of the 11 cancers we identified which were increasing and linked to known lifestyle factors—the most common by far in younger adults was breast cancer,” the study’s lead author, professor Montserrat Garcia-Closas, MD, DrPH, told Inside Precision Medicine. Garcia-Closas is in Integrative Cancer Epidemiology, Division of Genetics and Epidemiology, and The Cancer Epidemiology and Prevention Research Unit, The Institute of Cancer Research, London.

The rising incidence of certain cancers among people under 50 isn’t unique to England, and one major question is whether changes in behavioral risk factors might be to blame.

This research group analyzed cancer incidence trends in England from the National Disease Registry Service for the period 2001 to 2019, comparing patterns by sex in two age groups: 20–49 year olds and those aged 50+ for more than 20 different cancer types.

This database, “Captures virtually every cancer diagnosis in England going back decades—one of the most complete registries in the world. That scale is what allows us to track trends reliably across the whole population, not just a sample,” said Garcia-Closas.

The team used national health surveys to look at trends in established risk factors: smoking, alcohol intake; diet (high red/processed meat, low fiber intake), excess weight (BMI), and physical inactivity to quantify any changes by age and sex and estimate the proportion of cancers attributable to specific risk factors.

Their analysis showed that new cases of 16 out of 22 cancers in younger women, and 11 out of 21 cancers in younger men, increased significantly in England between 2001 and 2019. 

And five cancers—endometrial, kidney, pancreatic, multiple myeloma, and thyroid cancer— increased significantly faster in younger than in older women, while multiple myeloma increased faster in younger than in older men. 

But with the exception of excess weight, trends in these risk factors over the past one to two decades have been stable or improving for younger adults, with the largest reductions of around 7% in red meat consumption. 

The average daily amount of red meat eaten, they report, fell from 38 grams in 2008 to 17 grams in 2018 among younger men, and from 22 grams to 10 grams in younger women. And average processed meat intake in younger women was half that of younger men: 10 grams versus around 20 grams. And while more than 90% of younger adults weren’t eating enough fiber in 2018, their intake remained stable or slightly improved in both sexes between 2009 and 2019. And these trends were similar in older adults. 

Established behavioral risk factors accounted for a substantial share of cancer cases. In 2019 these contributed 68%–65% of mouth cancers for younger and older men, respectively; 42%–48% of liver cancers; 49%–53% of bowel cancers, 29%–33% of kidney cancers, and 36%–34% of pancreatic cancers.  

Among women they accounted for 52%–45% of mouth cancers; 35%–42% of endometrial cancers; 44%–46% of liver cancers; 38%–42% of bowel cancers; 33%–37% of kidney cancers; 31%–28% of pancreatic cancers; and 19% to 24% of gallbladder cancers. 

Excess weight was the risk factor associated with most cancers in 2019, ranging from 5% for ovarian cancer to 37% for endometrial cancers. 

“These patterns suggest that while similar risk factors across ages are likely, some cancers may have age-specific exposures, susceptibilities, or differences in screening and detection practices,” write the researchers.

“Prevention takes a long time and we must act now with what we know, with better and more effective public health policy and programs to address the overweight and obesity epidemic,” said Garcia-Closas.

The post Bowel and Ovarian Cancer Cases Rise Among U.K. Young Adults appeared first on Inside Precision Medicine.

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Bibliometric analysis of neurite orientation dispersion and density imaging: research patterns, evolution, and frontier

BackgroundNeurite orientation dispersion and density imaging (NODDI), an emerging diffusion MRI technique for estimating the microstructural pathology of brain tissue in vivo, has attracted significant research interest. However, a systematic bibliometric analysis of this field remains unexamined. This study aims to perform a bibliometric analysis of the NODDI literature to explore the current research landscape, identify emerging trends, and provide insights for future investigations.MethodsNODDI-related publications were retrieved from the Web of Science (WOS) and Scopus databases during the period of 2012 to 2025. CiteSpace, VOSviewer, and Bibliometrix R package were used to generate visualization maps.ResultsA total of 679 publications related to NODDI were identified from WOS, including 653 research articles and 26 review papers. 844 relevant publications were retrieved from the Scopus database. After 2012, the number of publications on NODDI increased rapidly. Sweden demonstrated the highest average citation per paper, while the United States contributed the largest number of publications. University College London was the most productive institution. Hui Zhang was identified as the most prolific author, while Alexander DC achieved the highest average citation count. NeuroImage was recognized as the leading journal in terms of publication frequency. Common keywords included “diffusion magnetic resonance imaging,” “NODDI,” “brain,” and “multiple sclerosis.” Recent studies show the research focus is shifting from methodological development to clinical application, especially in the field of neuropsychiatric disorders, and is being integrated with emerging methodologies such as Mendelian randomization.ConclusionsThis bibliometric analysis highlights potential directions for future NODDI-related research. Future studies may focus on optimizing imaging techniques, investigating neuropsychiatric disorders, and integrating advanced methodologies.
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‘Type’ Casting: Flagship-Founded Serif Modifying DNA into New Therapy Class

What happens when the scalability and redosability of messenger RNA (mRNA) is combined with the durability and programmability of gene therapy?

According to Serif Biomedicines, a five-year-old startup that emerged from stealth mode this month, the result is “modified DNA,” a new class of therapeutics designed to be programmable, durable, scalable, and redosable—while minimizing the drawbacks of both mRNA and gene therapy.

Modified DNA builds upon generative protein and mRNA platforms created by Flagship Pioneering, the venture capital giant which founded Serif in 2021. On April 21, Flagship formally launched Serif with an initial commitment of $50 million in financing—capital that Serif intends to use toward developing its scalable platform for optimizing and manufacturing Modified DNA treatments, aided by artificial intelligence (AI), and advancing its first drug discovery programs.

“The reason we’re bringing the company out of stealth mode now is we think we have made progress. We’ve made real progress that we’re excited to share with the world, that we’re excited to get feedback from the broader scientific community on, and we want to tell that story more broadly,” Jacob (Jake) Rubens, PhD, Serif’s co-founder and CEO, and an Orig­i­na­tion Part­ner at Flag­ship Pio­neer­ing, told GEN.

“It’s been on our minds for a long time: What might be possible when DNA becomes an engineerable biotechnology for the first time?”

It’s a question pursued by numerous researchers and companies over the years as they sought to capitalize on DNA’s qualities of being a durably expressing molecule capable of coding for any gene, producing proteins or RNAs in a cell-specific way, as well as being scalable to manufacture and capable of re-dosing for patients.

“Those are, I think, the key differentiating attributes of theoretical DNA medicines. So the question for us became not, would this be valuable if we could do it, but why hasn’t anyone done it yet?” Rubens explained. “We’ve known about the centrality of DNA in biology, the central information molecule in DNA. We’ve known this for 75 years since Watson and Crick’s seminal discoveries around how the structure of DNA enabled it to function as an information molecule.”

Two key problems

Jacob (Jake) Rubens, PhD, Serif Biomedicines co-founder and CEO

“And when we looked at this space,” he continued, “we saw that there were two key problems: The first is that DNA is a highly inflammatory molecule. The second is that DNA needs to be delivered not just into a cell, but into the nucleus, the center of the cell.”

To create Mod­i­fied DNA, Serif alters the struc­tur­al and chem­i­cal form of DNA in order to min­i­mize innate immuno­genic­i­ty as lipid nanoparticles drop off the DNA not in the nucleus, but in the cytoplasm of the cell.

Once inside the cell nucleus, Mod­i­fied DNA reverts to unmod­i­fied DNA, enabling tran­scrip­tion into ther­a­peu­tic RNA and proteins. The resulting treatments are designed to last longer, be giv­en more than once, and be pro­grammed for cell-spe­cif­ic expres­sion. To enhance durability, Serif delivers with its Mod­i­fied DNA proteins which help the DNA access the nucleus. The proteins, called mRNA co-fac­tors, are designed to tran­sient­ly express pro­teins that enhance entry into the nucleus and gene expression.

Pending an announcement it expects to make later this year, Serif isn’t revealing specifics of its initial drug discovery programs, except to say that they focus on rare diseases and immune programming.

“This is not meant to be a limited list of where we could go but the areas that we think we’re going to go first, which are likely in addressing protein deficiencies in genetic diseases,” Rubens said.

Modified DNA has shown itself to be disease agnostic, he added, reflecting DNA’s qualities as a general, programmable information molecule: “One of the reasons we’re so excited about, the future of modified DNA as a new biotechnology akin to RNA, akin to protein, is its centrality in biology. It is the fundamental information molecule inside of all of us, inside of every living thing on this planet. So that is really the existence proof that it is generalizable.”

Tolerability and sustained expression

Also later this year, Serif plans to present data at an as-yet-unspecified scientific conference that will show modified DNA’s tolerability in non-human primates, as well as sustained gene expression with therapeutic effects in preclinical models following intravenous (IV) administration.

Serif aims to transform Modified DNA into treatments as effectively and commercially successfully as Amgen, Genentech (now a member of the Roche Group), and later Regeneron did with engineered proteins, as Alnylam Pharmaceuticals did with small interfering RNA (siRNA), and as Moderna more recently accomplished with mRNA—most notably in developing its SpikeVax® COVID-19 vaccine, which the FDA authorized for emergency use in 2020 and fully approved in 2022.

Flagship launched Moderna in 2010; the company went public in 2018 by raising $604 million, the largest-ever U.S. biotech initial public offering (IPO) until Kailera Therapeutics raised $625 million earlier this month.

At Flagship, Rubens is a sci­en­tist entre­pre­neur who leads the firm’s Pio­neer­ing Busi­ness Unit, which establishes and grows com­pa­nies based on new biotechnology. In addition to Serif, Rubens co-founded Quo­tient Ther­a­peu­tics, which develops therapies based on its somatic genomics platform; Tessera Ther­a­peu­tics, which writes therapeutic messages into the genome through a genome engineering approach called GeneWriting™; and Sana Biotech­nol­o­gy, a developer of treatments based on engineered cells. He also launched Kalei­do Bio­sciences, a microbiome therapeutics company that ceased operations in 2022.

Before join­ing Flagship, Jake received his PhD in micro­bi­ol­o­gy from MIT, work­ing with Tim Lu, MD, PhD, a core member of the Synthetic Biology Center, through the sup­port of a Nation­al Sci­ence Foun­da­tion Grad­u­ate Research Fel­low­ship. At MIT, Jake helped enable ​“intel­li­gent” cell therapies by invent­ing gene cir­cuits that allow engi­neered cells to do nov­el ana­log, dig­i­tal, and hybrid com­pu­ta­tions.

Based in Cambridge, MA, Serif employs about 50 people and as of Wednesday was disclosing five open positions on its website in its three areas of focus: Chemistry (associate scientist and senior scientist, both specializing in LNP formulations), Molecular Biology (research associate and senior scientist), and Research/Discovery (scientist specializing in bioanalytical assays).

“I’m not at this point going to provide any guidance on how much more we will or won’t grow,” Rubens said. “We’re quite agile and responsive to the company’s needs.”

The post ‘Type’ Casting: Flagship-Founded Serif Modifying DNA into New Therapy Class appeared first on GEN – Genetic Engineering and Biotechnology News.

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Obesity Leaves Lasting DNA Methylation Memory in Immune Cells

A new study suggests that obesity leaves a durable molecular imprint on the immune system, one that persists long after weight loss and may continue to influence disease risk. Researchers at the University of Birmingham report that key immune cells retain an “epigenetic memory” of obesity, potentially sustaining inflammation and metabolic dysfunction even after patients return to a healthy weight.

The findings, published in EMBO Reports, provide a mechanistic explanation for a long-standing clinical observation: that individuals who lose weight often remain at elevated risk for conditions such as type 2 diabetes, cardiovascular disease, and certain cancers.

Immune cells retain a “memory” of obesity

The study focuses on CD4+ helper T cells, central regulators of immune coordination. By analyzing patient samples across multiple cohorts, including individuals undergoing pharmacological weight loss, rare genetic obesity syndromes, and lifestyle interventions, the researchers identified persistent epigenetic modifications in these cells.

Specifically, obesity was associated with changes in DNA methylation, a process in which chemical tags are added to DNA and alter gene expression without changing the underlying sequence. These modifications effectively encode a molecular memory of prior metabolic state.

As explained by the authors, these epigenetic marks can persist for years after weight loss. “The findings suggest that short-term weight loss may not immediately reduce the risk of some disease conditions associated with obesity,” said Claudio Mauro, PhD, senior author of the study. Instead, the immune system appears to retain a record of past metabolic stress that continues to influence cellular behavior.

Persistence beyond weight loss

The durability of this imprint is striking. The study estimates that obesity-associated DNA methylation patterns in T cells may persist for five to ten years after successful weight reduction. This suggests that immune remodeling lags far behind metabolic normalization.

Supporting this, the team observed similar patterns across diverse experimental systems, including human clinical samples and mouse models of diet-induced obesity. Together, these data point to a conserved biological mechanism rather than a transient or context-specific effect.

This persistent immune memory may help explain why relapse and long-term complications are common in obesity. As noted by Belinda Nedjai, PhD, of Queen Mary University of London, “the immune system retains a molecular record of past metabolic exposures, which may have implications for long-term disease risk and recovery.”

Disruption of cellular housekeeping and aging

At the functional level, the epigenetic changes identified in T cells appear to disrupt two critical biological processes: autophagy and immune senescence.

Autophagy, the process by which cells degrade and recycle damaged components, is essential for maintaining cellular health. The study suggests that obesity-associated DNA methylation impairs this pathway, reducing the cell’s ability to clear waste and maintain homeostasis.

In parallel, the researchers observed effects on immune aging, or senescence. Dysregulated T cells exhibited features of premature aging, potentially contributing to chronic inflammation and reduced immune resilience.

Together, these alterations could create a persistent pro-disease environment, even after weight loss. This reframes obesity not simply as a reversible metabolic state, but as a condition capable of inducing long-term immune reprogramming.

Implications for treatment strategies

The findings have direct implications for how obesity is managed clinically. If immune dysfunction persists for years after weight loss, then short-term interventions may be insufficient to fully restore health.

Instead, sustained weight maintenance—and potentially additional therapies targeting immune reprogramming—may be required. Mauro noted that “ongoing weight management following loss will see the ‘obesity memory’ slowly fade,” though this process may take years.

The study also points to potential therapeutic strategies. Drugs such as SGLT2 inhibitors, already used in diabetes treatment, may help accelerate the reversal of these epigenetic changes by reducing inflammation and promoting clearance of dysfunctional cells.

Rethinking obesity as a chronic immuno-metabolic disease

Beyond its immediate clinical implications, the study contributes to a broader conceptual shift in how obesity is understood. Rather than being defined solely by excess adiposity, obesity emerges as a condition that induces lasting systemic changes, particularly within the immune system.

As Andy Hogan, PhD, of Maynooth University emphasized, “obesity is a chronic progressive and relapsing disease,” and these findings help explain the biological basis of that persistence.

By identifying an epigenetic “memory” within immune cells, the work highlights a previously underappreciated dimension of metabolic disease: its capacity to reprogram immune function over the long term.

Looking ahead

The discovery of obesity-induced immune memory raises new questions about reversibility and intervention. Can these epigenetic marks be actively erased? And if so, how can therapies be designed to accelerate immune recovery?

Future research will likely focus on targeting these pathways directly, with the aim of restoring normal immune function and reducing long-term disease risk.

For now, the findings underscore a key message: losing weight is only part of the story. Fully reversing the biological impact of obesity may require sustained intervention—not just at the metabolic level, but at the level of the immune system itself.

The post Obesity Leaves Lasting DNA Methylation Memory in Immune Cells appeared first on Inside Precision Medicine.

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Anticancer Strategy Targets Defense Mechanism in Senescent Cells

Scientists headed by a team at MRC Laboratory of Medical Sciences (LMS) and Imperial College London have found that a new set of drugs can exploit a recently-revealed weakness in senescent—or ‘zombie-like’—cells, a finding that could lead to new treatments for cancer and age-associated diseases.

Senescent cells walk a tightrope, risking cell death with high levels of iron and other damaging agents, but compensating for this by overproducing a protective protein, GPX4, which staves off death. The team showed that targeting this defense mechanism removes the shield and could be used to treat diseases that are associated with senescence, including cancer. Tests showed that combining anticancer therapies with GPX4 inhibitors eliminated senescent tumor cells in models of melanoma, prostate and ovarian cancer. This approach, they say, could complement existing treatments to bring much-needed improvements for cancer patients.

Mariantonietta D’Ambrosio, PhD, a postdoctoral researcher at the LMS, is first author of the international research team’s published paper in nature cell biology, titled “Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.”

Cancers grow as a result of unconstrained cell division. But within most tumors, there is a portion that does not divide at all: senescent cells. Chemotherapy often increases the proportion of senescent cells in a tumor as it aims to stem the rapid proliferation, the team explained. However, while these senescent cells don’t directly increase the size of a tumor, they can wreak havoc in their own way.

Senescent cells, which are also a defining feature of aging conditions such as fibrosis, influence neighboring cells by secreting molecules that increase proliferation, the spread of the cancer, and unwanted immune system activity. “Senescent cells drive aging and age-related pathologies, including cancer,” the team wrote. There is therefore an increasing interest in developing drugs that directly target and kill senescent cells, in cancer and beyond. “Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal,” they continued. “Compounds that selectively kill senescent cells (senolytics) can treat different age-related pathologies.”

The study by D’Ambrosio and colleagues has identified a new approach to killing senescent cells in cancer.  “Senescence was considered for a long time to be positive, because senescent cells don’t proliferate, which is the core feature of cancer,” D’Ambrosio explained. “Normal chemotherapy induces senescence blocking the proliferation of cancer cells, so the tumor doesn’t get bigger. But with time you also see the negative side of the senescent cells, because they secrete a lot of factors that influence neighboring cells and induce even more proliferation, metastasis, and recruitment of bad parts of the immune system that will provoke even more aggressiveness in the tumor.  For this reason, we tried to find some drugs that were able to kill the senescent cells.”

The researchers cast a broad net in their search for new drugs that might kill senescent cells. Together with collaborators at the Department of Medicinal Chemistry at Imperial, they decided to examine covalent compounds, a class of inhibitors that can form a covalent bond with their target, which can result in the inhibition of proteins previously considered undruggable. The investigators introduced 10,000 different covalent compounds to both senescent cells and normal cells, looking for the ones that preferentially killed senescent cells and classing the drug as “senolytic,” or senescent-killing.

They narrowed their results down to just four promising compounds and found that three of them affected a particular protein, GPX4, which has a protective role in cells, helping stave off ferroptosis, a type of cell death associated with high levels of iron and destructive reactive oxygen species. To protect themselves against the high levels of iron and other ferroptosis-causing agents, senescent cells have high levels of GPX4. It is like proactively taking a painkiller so a person can keep running on an ankle. The damage and danger remains, but the immediate risks are bypassed. Removing the painkiller makes the pain unbearable.

“Senescent cells are primed for ferroptosis and upregulate GPX4 as a protective mechanism,” the team noted. Ferroptosis had only recently been revealed as a potential weakness of senescent cells. D’Ambrosio commented, “recent papers have shown this predisposition of senescent cells to ferroptosis, but it’s a new senescence vulnerability. That creates an opportunity for us to exploit. So now there is research to find senolytic drugs to kill cells through ferroptosis.”

The researchers found that blocking the activity of GPX4 removes the shield, making fatal ferroptosis unavoidable. The authors further commented, “We concentrated our studies on four chloroacetamides displaying senolytic activity in different models of senescence … GPX4 was a target of three of the four senolytic chloroacetamides. GPX4 is a glutathione peroxidase that prevents ferroptosis by reducing lipid peroxidation.”

The team tested their drugs with three different mouse models of cancer and saw improved outcomes as a result of senescent cell death in each case. Translating this to patients could be a huge asset to cancer treatments. “In mouse models we saw that these drugs reduced tumor size, and improved survival,” noted professor Jesus Gil, PhD, senior author and head of the senescence group at the LMS. “Now we need to see the effect on the immune system. Is the improvement also awakening the ‘good side’ of the immune system (T cells, natural killer cells) that helps to kill the tumor? … Once we know more, the next step is to understand which cancer cell types or specific patients might better respond to this treatment. For example, if a patient undergoing chemotherapy overexpressed GPX4 then you could use this approach in combination with existing drugs to improve efficacy.”

This approach offers a much-needed new perspective on cancer therapy, pinpointing senescent cells as an underexploited target. D’Ambrosio says it has potential to transform treatment. “Targeting senescence is a huge opportunity for cancer treatments, and ultimately it can play a supporting role in addition to chemotherapy and immunotherapy.”

The post Anticancer Strategy Targets Defense Mechanism in Senescent Cells appeared first on GEN – Genetic Engineering and Biotechnology News.

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The missing step between hype and profit

This story originally appeared in The Algorithm, our weekly newsletter on AI. To get stories like this in your inbox first, sign up here.

In February, I picked up a flyer at an anti-AI march in London. I can’t say for sure whether or not its writers meant to riff on South Park’s underpants gnomes. But if they did, they nailed it: “Step 1: Grow a digital super mind,” it read. “Step 2: ? Step 3: ?”

Produced by Pause AI, an international activist group that co-organized the protest, it ended with this plea to the reader: “Pause AI until we know what the hell Step 2 is.” 

In the South Park episode “Gnomes,” which first aired in 1998, Kenny, Kyle, Cartman, and Stan discover a community of gnomes that sneak out at night to steal underpants from dressers. Why? The gnomes present their pitch deck. “Phase 1: Collect underpants. Phase 2: ? Phase 3: Profit.”

The gnomes’ business plan has since become one of the greats among internet memes, used to satirize everything from startup strategies to policy proposals. Memelord in chief Elon Musk once invoked it in a talk about how he planned to fund a mission to Mars. Right now, it captures the state of AI. Companies have built the tech (Step 1) and promised transformation (Step 3). How they get there is still a big question mark.

As far as Pause AI is concerned, Step 2 must involve some kind of regulation. But exactly what it will call for and who will enforce it are up for debate.

AI boosters, on the other hand, are convinced that Step 3 is salvation and tend to glaze over the middle bit. They see us racing toward sunny uplands on the back of an “economically transformative technology,” as OpenAI’s chief scientist, Jakub Pachocki, put it to me a few weeks ago. They know where they want to go—more or less: It’s hazy up there and still some way off. But everyone’s taking a different route. Will they all make it? Will anyone?

For every big claim about the future, there is a more sober assessment of how the rubber meets the road—one that quells the hype. Consider two recent studies. One, from Anthropic, predicted what types of jobs are going to be most affected by LLMs. (A takeaway: Managers, architects, and people in the media should prepare for change; groundskeepers, construction workers, and those in hospitality, not so much.) But their predictions are really just guesses, based on what kinds of tasks LLMs seem to be good at rather than how they really perform in the workplace.   

Another study, put out in February by researchers at Mercor, an AI hiring startup, tested several AI agents powered by top-tier models from OpenAI, Anthropic, and Google DeepMind on 480 workplace tasks frequently carried out by human bankers, consultants, and lawyers. Every agent they tested failed to complete most of its duties.   

Why is there such wide disagreement? There are a number of factors. For a start, it’s crucial to consider who is making the claims (and why). Anthropic has skin in the game. What’s more, most of the people telling us that something big is about to happen have reached that conclusion largely on the basis of how fast AI coding tools are getting. But not all tasks can be hacked with coding. Other studies have found that LLMs are bad at making strategic judgment calls, for example.

What’s more, when they’re deployed, the tools aren’t just dropped into a cleanroom. They need to work in places contaminated with people and existing workflows. And sometimes adding AI will make things worse. Sure, maybe those workflows need to be torn up and refashioned around the new technology for it to achieve transformative status, but that will take time (and guts).  

That big hole? It’s right where Step 2 should be. The lack of agreement on exactly what’s about to happen—and how—creates an information vacuum that gets filled by the latest wild claim of the week, evidence be damned. We’re so unmoored from any real understanding of what’s coming and how it will be deployed that a single social media post can (and does) shake markets.

We need fewer guesses and more evidence. But that’s going to require transparency from the model makers, coordination between researchers and businesses, and new ways to evaluate this technology that tell us what really happens when it’s rolled out in the real world.

The tech industry (and with it the world’s economy) rests on the held-out promise that AI really will be transformative. But that is not yet a sure bet. Next time you hear bold claims about the future, remember that most businesses are still figuring out what to do with their underpants.