Beyond Cas9: Gene Editing's Second Act Spans Pig Kidneys to Stem Cells

In March 2026, Japan granted conditional, time-limited approval to raguneprocel, the world's first approved medicine derived from induced pluripotent stem cells — a marker of how far the field has moved since the FDA approved the first CRISPR-based treatment, Casgevy, for sickle cell disease in December 2023. That approval settled the question of whether gene editing can become medicine. The open questions now are narrower and harder: how to edit without cutting DNA, how to install whole genes rather than single letters, and how to replace cells that are already dead. Four companies and one university group laid out their answers, and each carries specific numbers that R&D managers can weigh.

Why move past conventional CRISPR?

Conventional CRISPR-Cas9 systems have two structural limits. They introduce DNA breaks that can cause unwanted deletions or rearrangements, and they cannot easily reach muscle and brain cells. Editing also cannot replace neurons or retinal cells that a disease has already destroyed.

What does eGenesis's pig kidney data show?

Xenotransplantation — transplanting organs between species — is not new; the first animal-to-human attempts occurred more than 60 years ago and failed within minutes to hours from immune rejection. What changed, according to Mike Curtis, CEO of eGenesis, is editing precision. "CRISPR really opened the door to precise gene editing, which has given us the ability to engineer pig organs that are more compatible with the human body," he said.

The company has made three classes of edits to its donor pigs:

• Inactivation of genes encoding human-incompatible carbohydrates on organ surfaces. "In our studies, a pig kidney modified in this way has been able to function in a human for several days to weeks without hyperacute rejection," Curtis said.
• Insertion of human genes to improve immune response to the organ.
• Inactivation of endogenous porcine retroviruses, addressing crossover infection risk.

Its most advanced kidney program has published first-in-human transplants in The Lancet (Riella et al., 2026). One high-risk dialysis patient supported by a pig kidney for nine months improved enough to receive a human transplant and was doing well eight months later. The Phase I/II/III RESTORE kidney trial is expected to initiate in the first quarter of 2027, and a first pig-to-human heart transplant is expected in 2027, following multiyear baboon studies. A liver program perfuses patient blood through an external pig liver as bridge support. Curtis frames the end goal plainly: "One of our ultimate goals is to produce animal organs that require no immunosuppression." The company stays tool-agnostic — Cas9, base editing or prime editing — judging edits by outcome.

Can editing work without cutting DNA?

Epicrispr bets it can. Its platform uses a deactivated, non-cutting nuclease called CasONYX, fused to modulator molecules that methylate DNA or add histone marks. "We bind to the gene with CRISPR-Cas technology and tell the DNA what to do. Should the gene be expressed more, less, or not at all? All without cutting the DNA strands," said CEO Amber Salzman, PhD. The small size of CasONYX and its modulators lets the system fit into adeno-associated viruses, which reach muscle, eye and brain — the tissues conventional CRISPR struggles to access. Studies suggest the modifications can persist indefinitely.

The lead indication is facioscapulohumeral muscular dystrophy (FSHD), a disease of reduced methylation at the D4Z4 repeat region that permits expression of the toxic DUX4 protein. Delivered by AAV to muscle, the system remethylates the region to suppress DUX4. "In patients with less-advanced disease, we can correct enough cells to stop DUX4 production and see a gain in lean muscle volume," Salzman said. Earlier-stage programs include a utrophin-upregulation approach for Duchenne muscular dystrophy (utrophin can compensate for dystrophin, which is too large for AAV packaging), in vitro activation of the neuroprotective SORL1 gene in Alzheimer's neuronal cells, and preclinical work in retinitis pigmentosa. Salzman argues the mechanism itself carries a safety edge: "When you are cutting, you can have genomic instability. Instead, we just make epigenetic marks."

Where do integrases fit?

Jesse B. Owens, PhD, of the University of Hawaii at Manoa and chief scientific advisor to KOMO Biosciences, draws the dividing line by cargo size. "I think the next phase of genome engineering will be less about changing one letter at a time and more about installing complete genetic programs," he said. His laboratory-directed-evolution integrases insert gene-sized DNA at defined genomic addresses without leaving an exposed double-strand break. "An integrase is like a molecular paste function," he added.

The measured result: evolved integrases hit the desired genomic destination 80% of the time, according to Owens's publications. Efficiency matters most when delivery is scarce, he argues, because a hyperactive enzyme gives scarce DNA payloads a better chance of correct insertion. Current partners are focused on CAR T and other engineered immune-cell therapies, where a single cassette must carry multiple receptors, persistence factors and a safety switch. The same chemistry applies to cell-line development and biomanufacturing, where predictable insertions could compress timelines. "KOMO's capacity for full gene replacement allows one product to address many different mutations in the same gene, rather than designing a separate editor for every patient's mutation," Owens noted.

What can stem cells do that editing cannot?

"In advanced degenerative neurologic and eye conditions, critical target cells have already degenerated and died," said Alex Solyom, MD, of Sumitomo Pharma America. Editing cannot regenerate tissue that no longer exists. Sumitomo's DSP-3077, now in Phase I/IIa trials, is an off-the-shelf iPSC-derived retinal sheet for retinitis pigmentosa, grown from a three-dimensional retinal organoid and delivered by a single subretinal injection designed to engraft and replace degenerated photoreceptors. It received FDA Orphan Drug Designation in March 2026. Raguneprocel, the dopaminergic iPSC product approved in Japan that same month as AMCHEPRY for Parkinson's motor symptoms, provides the proof of concept. "With iPSC-derived regenerative therapies, we aim to reestablish functional cells and tissue regardless of the underlying genetic mutation," Solyom said.

The common thread across all four programs is measurable progress on limits that conventional CRISPR cannot solve, and the next two years — RESTORE's launch, a first pig heart transplant, and DSP-3077's early trial data — will test whether these second-generation platforms hold their claims.