Beyond Conventional CRISPR

In December 2023, the FDA approved the first CRISPR-based treatment in the United States for sickle cell disease.¹ Despite this advance, conventional CRISPR-Cas9 systems may introduce potentially harmful DNA breaks and cannot easily be delivered to muscle and brain cells. Moreover, genome editing is not designed to replace neurons or retinal cells that have already been lost. In this article, experts from four companies discuss how they are moving beyond conventional CRISPR to develop novel approaches for treating disease.

Pig organs save lives

Xenotransplantation involves transplanting an organ from one species into another, explains Mike Curtis, CEO of eGenesis.

“There are just not enough human organs to satisfy the human need for kidneys, livers, lungs, and hearts,” he notes. “Xenotransplantation opens up a new supply of animal organs.”

Curtis explains how the first animal organs were transplanted into people more than 60 years ago. However, these organs were rejected within minutes to hours because of immune compatibility challenges.

Curtis emphasizes how advances in gene editing over the past 15 years have enabled xenotransplantation. “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 says.

The company has made three classes of CRISPR-based gene edits to modify its pig organs for human use. First, it inactivated genes encoding for human-incompatible carbohydrates on the surface of pig organs. “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,” says Curtis.

The second class of edits introduced human genes into the pig genome to improve the human immune response to the animal organ. Finally, the third class of edits inactivated endogenous retroviruses in the pig genome, alleviating concerns that infectious diseases could cross over from pigs to people.

eGenesis’s most advanced program is for the kidney. The company’s recent publication in The Lancet describes the first few transplants of pig kidneys into people.²

Curtis recalls one patient in the study. “This gentleman was doing poorly and had a very high risk of dying on dialysis. He was on the pig kidney for nine months, which improved his condition. He was then able to receive a human kidney transplant and is doing great eight months later.” The company is embarking on its Phase I/II/III RESTORE kidney trial, expected to initiate in the first quarter of 2027.

eGenesis’s second program involves the liver. The patient’s blood is perfused through a pig liver located outside of the body. This procedure provides life support and allows the person’s liver to recover while a human liver becomes available.

Finally, eGenesis is hoping to tackle end-stage heart failure. For the past couple of years, the company has been studying the long-term effects of pig heart transplants in baboons. Its first pig-to-human heart transplant is expected in 2027.

Is eGenesis finished with its gene edits? “One of our ultimate goals is to produce animal organs that require no immunosuppression,” says Curtis. “The only way to achieve that goal is iterative gene editing based on our first generation of organs. If we have our way, it should only get better from here.”

Although most of eGenesis’s edits have used CRISPR technology, the company is agnostic about the specific gene-editing tool. “Our goal is to improve the compatibility of pig organs for human recipients. The specific tool we use, whether it is Cas9, base editing, or prime editing, matters less to us than the outcome,” Curtis notes.

Epigenetic editing

While DNA contains the instructions for gene expression, epigenetic tags—such as DNA methylation and histone acetylation—act like switches that turn genes on and off. Epigenetic modifications help explain why people with the same genetic mutation may experience very different outcomes.

“We are leveraging the power of the epigenome to create new therapeutic possibilities,” explains Amber Salzman, PhD, CEO of Epicrispr. She notes how the first generation of CRISPR technology was designed to cut DNA and remove faulty genes.

“In contrast, 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.”

Instead of the Cas9 nuclease used in first-generation CRISPR technologies, Epicrispr’s platform utilizes a much smaller molecule called CasONYX, which is deactivated and unable to cut DNA.

The platform fuses what it calls a modulator to each deactivated Cas nuclease. “These molecules will methylate DNA or put on histone modifications,” notes Salzman. Studies suggest that these modifications can potentially last indefinitely. And because Epicrispr’s Cas molecules and modulators are so small, they can fit into adeno-associated viruses (AAVs), which can access the muscles, eyes, and brain.

The company’s lead indication is facioscapulohumeral muscular dystrophy (FSHD). “We are the only company going after the root cause in FSHD, which is fundamentally a disease of reduced methylation,” Salzman notes.

More specifically, FSHD is associated with fewer repeats in the D4Z4 region of the genome and a looser chromatin architecture. This structure allows for the expression of the toxic DUX4 protein, which kills muscle cells.

Epicrispr’s FSDH machinery is delivered to the muscle with an AAV. The region is then remethylated to suppress the genes responsible for DUX4 expression. “In patients with less-advanced disease, we can correct enough cells to stop DUX4 production and see a gain in lean muscle volume,” says Salzman.

The company also has early preclinical data on Duchenne muscular dystrophy. A major challenge in treating this condition is that the faulty dystrophin protein is too large to fit into AAVs. However, a protein called utrophin can compensate for a lack of dystrophin.

“We deliver a construct to the muscle cells with an AAV vector that instructs utrophin to be expressed at high levels and make up for the lack of dystrophin,” she notes.

Epicrispr has generated in vitro data for Alzheimer’s disease showing the activation of the SORL1 gene in neuronal cells. This gene has been shown to be neuroprotective in the disease. It also has promising preclinical results for retinitis pigmentosa, an eye disease caused by a faulty protein called rhodopsin.

Finally, Salzman argues that Epicrispr’s strategy may be safer than traditional CRISPR. “When you are cutting, you can have genomic instability. Instead, we just make epigenetic marks,” she adds.

Inserting large genes

“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,” predicts Jesse B. Owens, PhD, assistant professor at the University of Hawaii at Manoa and chief scientific advisor of KOMO Biosciences.

While conventional CRISPR-Cas9 technology is excellent for small edits, the insertion of large amounts of DNA is far less efficient, he notes. Furthermore, CRISPR generates exposed DNA breaks that can cause unwanted deletions or rearrangements.

Integrases fill a different niche. They actively install gene-sized DNA at a defined site without leaving an exposed double-strand break. “An integrase is like a molecular paste function,” adds Owens. “It recognizes relatively long DNA addresses in the genome and actively inserts large fragments of DNA.”

“Integrases have been known for some time,” he continues. “The key difference is that our enzymes have been engineered with laboratory-directed evolution to be highly effective.” For instance, Owens’s recent publications demonstrate that evolved integrases can insert DNA into the desired genomic destination 80% of the time.

Owens stresses that the biggest remaining bottleneck for many therapeutic applications involves delivering the genetic editing machinery to the right cells. “A hyperactive integrase changes that equation,” he says. “When delivery is scarce, a much more efficient enzyme gives the DNA that reaches a cell a better chance of becoming a correct insertion.”

The company’s partners are currently interested in CAR T and other engineered immune-cell therapies. Such therapies often require large DNA insertions to fit multiple components for cancer therapy—including multiple receptors, persistence factors, and a safety switch within a single genetic cassette.

Beyond therapeutics, integrase technology has many applications in cell-line development and biomanufacturing. For instance, a highly efficient integrase-based system could create a more predictable starting cell-line population and compress development 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,” notes Owens.

Stem cell approval

“In advanced degenerative neurologic and eye conditions, critical target cells have already degenerated and died,” explains Alex Solyom, MD, vice president and head of clinical research, rare disease and biopharma at Sumitomo Pharma America. Interventions like CRISPR are not targeted to regenerate tissue structures that no longer exist in the patient.

Induced pluripotent stem cells (iPSCs) provide a supply of healthy cells to potentially replace or functionally restore damaged tissue. Researchers can generate them by reprogramming mature cells (such as skin or blood cells) back into an embryonic-like state. Importantly, iPSCs avoid ethical concerns associated with embryonic stem cells derived from fertilized eggs.

iPSCs provide a convenient basis for developing potential therapies. They can replicate endlessly in culture following reprogramming. They are also pluripotent, meaning that they can mature into virtually any specialized cell type.

“With iPSC-derived regenerative therapies, we aim to reestablish functional cells and tissue regardless of the underlying genetic mutation. This can be particularly important for diseases driven by mutations across multiple genes,” Solyom notes.

He highlights Sumitomo’s DSP-3077, an investigational iPSC therapy being developed as an off-the-shelf cell therapy for patients with retinitis pigmentosa, a progressive genetic eye disorder in which retinal photoreceptors degenerate.

Currently in Phase I/IIa trials, DSP-3077 consists of an iPSC-derived retinal sheet produced from a three-dimensional retinal organoid. This organoid is formed during a proprietary self-organizing process in which required cell types are differentiated from the iPSCs.

A single subretinal injection inserts the sheets into the patient’s eye. The injected sheets are designed to physically engraft into the patient’s retinal tissue. “We believe this will support natural retinal tissue architecture and replace degenerated photoreceptors, potentially helping to restore visual function,” Solyom says. In March of 2026, the investigational therapy received an FDA Orphan Drug Designation.

Meanwhile, Sumitomo’s raguneprocel, a dopaminergic neural cell product, is the world’s first approved iPSC-derived medicine. In March 2026, it received conditional, time-limited approval as AMCHEPRY^® in Japan to improve motor symptoms in Parkinson’s disease.

“Being able to deliver to patients functional tissue made up of a complex structure and multiple cell types—and derived from the same stem cell line—is a worthwhile challenge and a great accomplishment drawing on decades of research,” concludes Solyom.

References

1. Singh A, Irfan H, Fatima E, et al. Revolutionary breakthrough: FDA approves CASGEVY, the first CRISPR/Cas9 gene therapy for sickle cell disease. Ann Med Surg (Lond). 2024;86(8):4555-4559. doi: 10.1097/MS9.0000000000002146.

2. Riella LV, Borges TJ, Rosales IA, et al. Porcine kidney xenotransplantation as a bridge to allotransplantation: a first-in-human study. Lancet. 2026;408(10559):1029-1040. doi: 10.1016/S0140-6736(26)01295-X.

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