A recurring theme Tuesday morning at Phacilitate’s Advanced Therapies Week was the quickly emerging potential of in vivo approaches to cell and gene therapy—a trend also reflected in recent investments by Eli Lilly and Regeneron.
In vivo cell and gene therapy is en vogue at Phacilitate’s Advanced Therapies Week in San Diego this week, a theme that reflects a recent rush of activity in the space, including Eli Lilly’s $2.4 billion acquisition of Orna Therapeutics on Monday.
“In vivo is the new allogeneic,” Susan Nichols, CEO of Propel Bio, a commercialization acceleration partner, said during Tuesday’s kickoff session, which convened Phacilitate’s advisory board to discuss 2025: What Worked. What Didn’t. What Comes Next?
While ex vivo cell therapy involves extracting patient cells, modifying or engineering them outside the body and then reinfusing them into the patient, in vivo approaches deliver the therapeutic payload directly into the patient’s body, bypassing this step.
In vivo cell and gene therapies have “huge promise [and] heavy investment,” Nichols continued, though she added that human data is limited for now. “As one advisor put it, in vivo approaches are full of promise, but the investment momentum is outpacing the clinical data.”
While in vivo cell and gene therapy (CGT) approaches might be early-stage, Big Pharma—including obesity darling Eli Lilly—is buying in. In the past, issues around accessibility had limited Lilly’s interest in the modality.
“The data is amazing,” Lilly CEO David Ricks told Reuters in 2019, “but practically, it’s not reaching many people.”
Lilly appears to believe that Orna’s technology, which uses circular RNA paired with novel lipid nanoparticles to enable a patient’s own body to generate cell therapies, can solve this challenge.
“We look forward to working with Orna colleagues to potentially unlock an entirely new class of genetic medicines and cell therapies for patients who today have limited or no treatment options,” Francisco Ramírez-Valle, head of Immunology Research and Early Clinical Development at Lilly, said in a statement.
Negating the Need for Chemotherapy
Victoria Gray, a patient advocate who was the first person with sickle cell disease (SCD) to be treated with Vertex Pharmaceuticals’ and CRISPR Therapeutics’ CRISPR-based gene editing treatment Casgevy, told BioSpace that in vivo gene therapy could be available to more people because it negates the need for immunosuppressive chemotherapy.
“I would love to see the science advance for patients like myself” who are currently required to undergo a conditioning regimen with a chemotherapeutic agent, Gray said during a patient advocacy session at Advanced Therapies Week on Tuesday. That agent, busulfan, is used to destroy the defective blood stem cells in the bone marrow to make way for the edited cells. Both Casgevy and Genetix Bio’s (formerly bluebird bio) Lyfgenia come with this caveat. “That was the hardest part for me,” Gray said.
Kristen Hege, former senior vice president of Early Clinical Development, Hematology/Oncology & Cell Therapy at Bristol Myers Squibb, emphasized the long-term impact of lymphodepletion treatment.
“When we think about in vivo gene therapy, I think a lot of people talk about patient access, cost of goods, but there’s more than that,” she said during a session titled: We’ve solved for science. What now? The chemotherapy that’s required before the infusion of ex vivo CAR T cells can cause immune suppression that can last for weeks, she continued. This can “increase the risk of infection, and we don’t really talk about it, but [can also] cause leukemia. Eliminating the need for lymphodepleting chemotherapy, if it pans out with in vivo, could be another real advantage.”
Indeed, the approach is catching on. In addition to Lilly, Regeneron also recently bought into the in vivo approach, linking up with Cambridge, Mass.–based Tessera Therapeutics late last year. The partnership is aimed at advancing the in vivo editor TSRA-196 for alpha-1 antitrypsin deficiency (AATD). Tessera is also developing a gene writer for SCD, Cell & Gene.com reported in January 2025, aiming to directly correct the mutation that causes cells to sickle through a one-time IV treatment.
But the potential advantages don’t stop with access and tolerability, according to Hege.
“Regulations are often built around what you can measure, and if you can measure it, then you’re required to measure it. Or if you can control it, then you’re required to control it,” she said. “I think that’s been one of the challenges for ex vivo manufacturing, because there’s a lot of things that you can measure and control.”
With in vivo approaches, Hege continued, “What happens in the patient is beyond your control, and therefore you’re not held to a standard” in terms of pharmacodynamic, phenotypic and gene expression endpoints as part of the product characterization.
“Belief is currently leading data, not following it,” Nichols said of in vivo treatments during her presentation.
Ultragenyx Pharmaceutical has long stood behind in vivo gene therapy. The rare disease–focused biotech presented new data last week from two trials of its novel in vivo AAV9 gene therapy UX111 at the WORLDSymposium 2026. The candidate, in development for Sanfilippo A syndrome, sustained cognitive improvements over up to eight years of follow-up, according to Ultragenyx’s Feb. 3 press release.
UX111 was rejected by the FDA in July 2025, but clinical data was not the issue. Rather, the agency wanted to see “improvements” in “certain aspects” of the therapy’s chemistry, manufacturing and controls,” Ultragenyx said in its announcement of the complete response letter.
“Regulation is no longer the gating issue,” Nichols concluded.