Cell And Gene Therapy Innovations

Last June, AbbVie paid $2.1B for Capstan Therapeutics, a Penn spinout co-founded by Drew Weissman (2023 Nobel laureate for mRNA work). Last week, Weissman's academic lab — with E. John Wherry and Michael Betts — published in Science Immunology, what may be the next chapter for in vivo CAR-T: targeting by cell state, not just cell type. The approach: decorate a lipid nanoparticle with fractalkine (CX3CL1), the ligand for CX3CR1, a chemokine receptor that marks cytotoxic effector CD8 T cells. The LNP finds the cell. The mRNA cargo is read transiently, then disappears. The data: • Up to ~90% of effector CD8 T cells targeted in mouse blood and spleen • Close to 100% in macaque peripheral blood • ~60% of targeted cells expressing the encoded protein • Payloads tested: GFP, IL-2 (mouse), CD62L (macaque) No permanent gene editing. No ex vivo manufacturing. A transient instruction, delivered to a defined immune-cell state (tested with 3 payloads so far). This paper is the academic-side mirror of a thesis Big Pharma has spent more than $14B backing in the last 14 months — AbbVie/Capstan ($2.1B), Lilly/Orna ($2.4B), Lilly/Kelonia (up to $7B), BMS/Orbital ($1.5B), AZ/EsoBiotec ($1B), Gilead/Interius ($350M). I wrote up the science and the commercial landscape in this week's newsletter. Link in the comments and thanks for the support as always :)

Researchers at Johns Hopkins University have created a revolutionary protein “switch” that tricks cancer cells into manufacturing their own chemotherapy drugs, causing them to self-destruct while sparing healthy cells. Instead of delivering drugs directly to cancer cells, this method uses a harmless “prodrug” that only becomes activated inside cancer cells when the switch detects specific cancer markers. The switch is made by combining two proteins: one that senses cancer markers and another from yeast that converts the inactive prodrug into a potent cancer-killing drug. When the switch detects cancer, it activates the drug inside that cell, turning the cancer cell into a drug factory that destroys itself. To work, the switch must enter cancer cells either by delivering the protein itself or by inserting the gene that makes the protein, allowing the cancer cell’s own machinery to produce the switch. Afterward, patients receive the inactive chemotherapy prodrug, which becomes activated only inside cancer cells. This new approach focuses on producing the drug inside cancer cells rather than just delivering it to them, which could kill more cancer cells while reducing harmful side effects on healthy tissue. Lab tests on human colon and breast cancer cells have shown promise, and animal testing is expected to start within a year. While still early, this technique offers a radically different way to attack cancer. #PNAS #RMScienceTechInvest

Scientists just deleted the extra chromosome in Down syndrome cells. 13% of treated cells went from three copies to two—partially resetting their genetic code. In a lab dish, not a person. But still. Think about that. Japanese researchers used CRISPR like a genetic eraser, targeting only the surplus chromosome 21. They removed it completely from human Down syndrome cells in the lab for the first time. The cells started behaving differently. Overactive genes calmed down. Brain development genes became more active. Gene expression moved toward typical levels—not perfect, but closer. Traditional Down Syndrome Reality: ↳ 1 in 700 births worldwide ↳ Extra chromosome 21 considered permanent ↳ Families navigating complex medical needs ↳ Prenatal screening, difficult decisions The CRISPR Breakthrough: ↳ Allele-specific targeting of just one chromosome ↳ 13% baseline success (up to 30% with modifications) ↳ Works in both stem and skin cells ↳ Gene expression shifts toward typical But here's what stopped me cold: They made multiple cuts along the targeted chromosome—like perforating paper before tearing. The cell's own machinery then discarded the damaged chromosome during division. When they cut all three chromosomes non-specifically? Cell survival plummeted. The technique works in non-dividing cells too. That opens theoretical doors—tissues that stopped multiplying years ago. Still far from any real application. What changes everything: ↳ Proof that trisomy can be reversed at cellular level ↳ Method could theoretically adapt to trisomies 13 and 18 ↳ From managing symptoms to addressing cause—in cells The weight of this sits heavy: Many families cherish their children exactly as they are while hoping for fewer medical complications. The disability community asks: Are we editing away diversity or suffering? No embryos. No fetuses. No humans. Just cells in dishes. Safety concerns—structural variants, genome damage—mean any therapy remains more research, more trials. The Multiplication Effect: 1 successful cell line = proof of concept 10 research teams refining = safety barriers to solve At scale = questions we're not ready to answering We spent decades accepting chromosomal conditions as unchangeable. Now CRISPR shows they might not be—at least in a petri dish. Because when you can subtract an entire chromosome from a living cell, you're not just editing genes. You're rewriting what we thought was permanent. Follow me, Dr. Martha Boeckenfeld for innovations where science meets ethics. ♻️ Share if you believe medical breakthroughs need wisdom, not just possibility. Resource: Trisomic rescue via allele-specific multiple chromosome cleavage using CRISPR-Cas9 in trisomy 21 cells. PNAS Nexus, 2025

India is proving that advanced therapies do not have to remain a luxury for the few. Cell and gene therapies have been hailed globally as breakthrough treatments for cancer and rare diseases, but their price has always been the barrier. In Europe and the US, CAR-T therapies routinely cost €300,000 to €400,000 per patient, placing them far beyond the reach of most families. This is why what is happening in India is so significant. I recently had the chance to speak with the team at ImmunoACT, and their work on NexCAR19 is a milestone for both science and access. • NexCAR19 launched at around €33,000 to €44,000 per treatment, an order of magnitude lower than Western counterparts • The company has publicly set its sights on reducing this further to as low as €22,000, making it one of the most affordable CAR-T therapies anywhere in the world • Already more than 350 patients have been treated across 70 hospitals in India • ImmunoACT also achieved profitability within its first year of operations, showing that affordability and sustainability can coexist in biotech. What stands out most to me is intent. The science is world class, but the mission is deeply human, to make transformative therapies accessible, not aspirational. From my perspective at myGrape, working on the supply chain side of advanced therapies, this affordability is only half the equation. A CAR-T therapy is not only about discovery in the lab, it is about ensuring every patient who needs it can actually receive it. That requires rethinking how these therapies are produced, transported, and delivered at scale, especially across diverse geographies. India has an opportunity not just to innovate, but to lead by example. If we can build therapies that are both cutting edge and affordable, supported by resilient and patient centric supply chains, then we can show the world what equitable access to medicine truly looks like. This is more than a breakthrough. It is a blueprint. Rahul Purwar Dr. Vivek Vikram Singh CA RAJAT MAHESHWARI Shobhit Purwar

Last month, a team of scientists and physicians achieved something extraordinary: they developed and delivered the first-ever personalized #CRISPR therapy to treat an infant with a life-threatening #raredisease — in just six months. A one-letter change in the baby’s DNA was corrected using a custom-built gene editor. The child, who was once facing the prospect of a liver transplant, is now steadily improving. It’s a powerful example of what’s becoming possible at the intersection of #science and #technology, urgency and purposeful ambition. And this isn’t an isolated win. Across labs, clinics, and companies, CRISPR is being used as a therapeutic modality to correct inherited disorders, engineer immune cells, disable viral DNA, and even edit entire chromosomes. New gene-editing systems—like TIGR-Tas, unveiled earlier this year—are expanding what’s possible in tissues or conditions where current tools fall short. Clinical results are emerging fast—and the pace of #innovation is only picking up. At Recursion, we’re also applying #geneediting tools like CRISPR beyond therapeutics—using the technology as a tool to better understand #biology at scale. By systematically “knocking out” thousands of individual genes and measuring how those changes affect cell behavior, we’re generating large, structured datasets that feed directly into #AI models. This is helping us uncover new biological relationships and power #drugdiscovery in ways that were previously unimaginable. What ties all of this together is a commitment to applying game-changing #innovation in service of real, urgent human needs. It signals a much-needed mindset shift in #healthcare and #biopharma: to move faster, think bigger, and tackle challenges once considered out of reach—and to truly deliver on the promise of #precisionmedicine. And we’re seeing this ambition in many other areas as well – just last week, for example, GRAIL announced more promising than ever performance stats for its #Galleri blood test for the early detection of 50+ types of #cancer. There’s still work ahead to ensure breakthroughs translate into broad, equitable impact. But this moment – this momentum – is worth pausing to recognize. We’re no longer just imagining a future where science works smarter and faster for patients. We’re building it.

🔥 A quiet but meaningful leap in cancer immunotherapy🔥 🔬 Scientists from the Chinese Academy of Sciences have unveiled a scalable way to mass-produce natural killer (NK) cells and CAR-NK cells, using CD34+ stem and progenitor cells from cord blood. Why this matters 👇 📍 Moves engineering upstream, at the stem cell stage 📍 Produces millions of uniform NK cells from a single progenitor 📍 Dramatically reduces viral vector use and cost 📍 Demonstrates strong tumour-killing activity in leukemia models In theory, a fraction of one cord blood unit could generate thousands of therapeutic doses. ⚛️ This is not hype. It is manufacturing science meeting immunology, turning personalised therapy into something closer to platform medicine. If CAR-T was the first act, CAR-NK may well be the scalable sequel. 💎 Progress in oncology is rarely loud. But it compounds.

T cell-specific non-viral DNA delivery and in vivo CAR-T generation using targeted lipid nanoparticles Methods Minicircle DNA (mcDNA) encoding a CAR construct and SB100x transposase mRNA were encapsulated within a novel lipid formulation which was functionalized with T cell-specific anti-CD7 and anti-CD3 binders. In vitro, we evaluated T cell specificity, mcDNA and mRNA transfection efficiency, transposon-mediated CAR integration and functionality of the resulting CAR-T cells. In vivo efficacy was assessed in peripheral blood mononuclear cell and CD34+ stem cell humanized murine xenograft models of B cell leukemia. Results In vitro, NCtx displayed high specificity and transfection efficiency with both mcDNA and mRNA in primary T cells. Transposase mRNA facilitated genomic integration of the CAR gene, leading to the generation of stable CAR-T cells that exhibited antigen-specific cytotoxicity and cytokine release. In vivo, a single intravenous dose of NCtx induced robust CAR-T cell generation resulting in effective tumor control and significantly improved survival in two distinct xenograft models. Conclusions Our findings demonstrate for the first time that targeted LNPs can be employed for efficient DNA delivery to T cells in vitro and in vivo. We show that when combined with transposase technology, this LNP-based system can efficiently generate stable CAR-T cells directly in vivo, inducing potent and durable antitumor responses. NCtx represents a novel non-viral gene therapy vector for in vivo CAR-T therapy, offering a scalable and potentially more accessible alternative to traditional approaches in CAR-T cell generation. Vertex Biopharm Consulting https://lnkd.in/ekCEXyBc

LNPs + mRNA = In vivo CAR-T? Not always. When we talk about LNP-mediated in vivo delivery, the conversation usually turns straight to in vivo CAR-T programs (like those from Capstan Therapeutics or CREATE Medicines). But a recent study corroborates a powerful alternative: mRNA-encoded T-cell Engagers (TCEs). Instead of re-engineering the T-cell itself, this approach turns the liver into a local "bio-factory" to produce bispecific antibodies in situ. The Breakdown (MTS105 for Hepatocellular Carcinoma): 🔹 The Cargo: mRNA encoding a bispecific T-cell engager (CD3 x GPC3) 🔹 The Vehicle: Liver-tropic Lipid Nanoparticles (LNPs).  🔹 The Mechanism: After IV infusion, hepatocytes uptake the LNPs and begin secreting the TCE protein directly into the tumor microenvironment. Why this matters: This creates high local concentrations in the liver and tumor while maintaining low systemic exposure, reducing cytokine release syndrome (CRS) and off-target toxicity. The Results: 🟢 Efficacy: Complete tumor regression in orthotopic HCC models (using humanized CD3EDG mice). 🟢 Safety: Favorable PK and toxicology profiles in Non-Human Primates (NHP).  🟢 Clinical: First-in-human trials are already underway (NCT06689540). The link to the full study is in the comments. 

Lipid nanoparticles have a gene delivery problem. But this hybrid approach radically improves that: (As in, 18x better) First, a quick review of the challenge: - Conventional LNPs struggle with intracellular delivery, with endosomal escape efficiency below 2.5% (read: most LNPs get chewed up by the cell) - Since so many of them get chewed up, nearly 70% actually get recycled and expelled from cells, without ever releasing their cargo - Overall, that means bad gene expression So how can this be fixed? The authors used microfluidics and dialysis to combine 2 different modalities together: - LNPs - Cell-derived vesicles The result: A hybrid delivery system: half LNP, half vesicle Key Findings: - The hybrid system 10x'd intracellular delivery compared to traditional LNPs. - Dramatically enhanced protein production in vitro and in vivo (18x). - The hybrids showed more direct movement within cells, reducing unwanted recycling. - Superior stability compared to normal LNPs - Similar distribution profile to conventional LNPs Seriously, this is pretty cool. Non-viral gene therapy hasn't made the strides we'd hoped for. This technique could be one of the factors to change that. Kudos to the authors, great work! What are your thoughts on this technique? Drop them in the comments.