ROME — The inclement weather has been a major topic this week among close to 3,000 delegates at the European Society of Cell and Gene Therapy (ESGCT) annual meeting in Rome.* Heavy rain midweek flooded the Rome subway, disrupting travel for delegates including those hungrily heading to the speakers’ dinner. A British presenter apologized for showing up late for his talk, explaining that he had been so engrossed in discussing the weather with a colleague that he completely lost track of time.
Then there was a sudden squall in the plenary hall, midway through a session on In vivo Gene Editing in Preclinical Models on Thursday, in which the CSO of Prime Medicine threw shade on the preceding speaker, his counterpart at Tessera Therapeutics. “It is great to follow Tessera,” said Jeremy Duffield, MD PhD, opening his talk, “because we can see they’re doing prime editing!”
Duffield made the point again in his closing remarks. “There are over 1,000 papers on prime editing, nothing on [Tessera’s] RNA writing. We know very little,” he said. “[It is] a Cas domain linked to a reverse transcriptase, so probably quite similar.”
The technology of prime editing was published five years ago in Nature by Andrew Anzalone, MD PhD, and colleagues in the lab of David Liu, PhD, at the Broad Institute. This ingenious precision editing platform using reverse transcriptase provided the means to engineer any potential single-base substitution in the genome. Liu and Anzalone co-founded Prime Medicine, which is working on several preclinical programs for Mendelian diseases.
Tessera Therapeutics was founded in 2018, building capabilities in what it calls “gene writing” and filing its first patent application. But over the past year or two, there have been questions around the potential similarity between Tessera’s core gene editing technology and prime editing. Indeed, this is not the first time that questions have been raised publicly about the relationship between Tessera’s RNA Gene Writers and Prime’s Editors.
In response to an inquiry from GEN, a Tessera spokesperson commented:
“Tessera’s platform is rooted in years of proprietary research and development and harnesses target primed reverse transcription (TPRT) to permanently edit the genome, a mechanism first elucidated in the 1980s and early 90s. Our innovative efforts have resulted in unique and proprietary compositions, and have enabled the exciting results featured in Dr. Holmes’ presentation. We are excited to advance our programs to the clinic to provide potentially curative therapies for patients with alpha-1 antitrypsin deficiency, sickle cell disease, and other diseases.”
Michael Holmes, PhD, joined Tessera as CSO almost three years ago. Holmes is a pioneer in genome editing, having been a key figure in the early demonstrations of genome editing in mammalian cells using zinc finger nucleases at Sangamo Therapeutics two decades ago.
In his short ESGCT presentation, Holmes skipped lightly over Tessera’s technology, briefly stating that it is inspired by retrotransposons, can introduce a broad range of edits, and that his colleagues had conducted evolutionary searches to identify proteins with key capabilities (such as RNA-binding and DNA-nicking), before stitching them together with RNA templates “to find unique RNA gene-writing editors.”
Holmes presented data on the use of RNA Gene Writers to tackle two genetic disorders: sickle cell disease (SCD) and α-1 antitrypsin deficiency. Unlike Casgevy, which relies on an ex vivo strategy, Tessera is pursuing an in vivo approach, using proprietary lipid nanoparticles (LNPs) to deliver the editing machinery to native hematopoietic stem cells; the benefits of this approach would be enormous, sparing patients from having to harvest stem cells or undergo myeloablative conditioning. That would open up the possibility “to treat a large fraction of [SCD] patients… millions worldwide,” Holmes said.
In the SCD program, Tessera is using RNA gene writers to directly target and reverse the SCD mutation. Experiments show levels of allele correction of approximately 75%, producing cells that can develop in vitro to form mature red blood cells. The strategy results in complete elimination of the sickle cell phenotype in red blood cells derived from treated CD34+ cells.
To extend the work in vivo requires the development of unique LNPs, in which Tessera is seeking to optimize the ionizable lipid, targeting strategy and formulation. These are being tested in humanized mice and NHPs. Holmes reported 76% allele correction in HSCs, which he judged to be “an incredible accomplishment.”
“We’re now up to 52% editing of the endogenous β-globin locus in a single dose. We’ve come a long way,” Holmes said. “We do think we’re hitting the true [HSCs].”
“This is a potential one-shot therapy for [SCD] patients,” Holmes said, one that could “transform the way patients are treated with these devastating diseases. Not having to do ex vivo manufacturing and not having to myeloablate patients [has been] a dream of mine for a very long time.”
In preclinical data for α-1 antitrypsin deficiency, Holmes and colleagues have used a pair of mouse models as well as a nonhuman primate (NHP) model. Levels of gene correction are within 64–82%, with signal-to-noise ratio of intended to unintended edits up to approximately 200:1 in humanized mice. Mouse models showed high levels of secreted functional protein in the serum. In NHPs, Holmes said the strategy corrected about 79% hepatocytes, with 84% RNA transcripts.
Prime position
Duffield, a British physician scientist who joined Prime Medicine four years ago from Vertex, followed Holmes by presenting preclinical data on two liver disease programs: Wilson’s Disease and glycogen storage disease (GSD) type 1. The delivery method is again an LNP using a GalNAc targeting ligand, which Duffield said has been “derisked and validated in humans… In our hands, this approach increases potency, safety profile, and biodistribution.”
Half of GSD patients have one of two mutations, which are being studied in humanized mice models. Duffield said successful prime editing produces phenotypic rescue with a dosing and safety profile “that is ready to take forward to patients.” Work continues in larger animal models, which requires some tinkering to develop guides that work in healthy primates.
The gene for Wilson’s disease was discovered in 1993. It is a disorder of copper transport, leading to toxic accumulation of copper in the liver and brain. Working in a humanized mouse model, iterations of prime editor development have resulted in 80% editing efficiency from a single infusion. Copper levels are halved after two weeks and fall to about 25% after a month. Duffield said his team is looking to achieve a 90% reduction. Work in NHPs seeks to introduce (rather than reverse) the mutation to test editing efficiency, as there is not an NHP model for the disorder. The editing works precisely, with no evidence of double-strand breaks.
“This should produce a full data package to take to the clinic rapidly,” Duffield concluded.
Next year, ESGCT moves to Seville, Spain (October 7–10, 2025). The forecast is warm sunshine with a chance of storms.
*ESGCT 2024; Rome Convention Center, Italy; October 22-25, 2024.
Oct. 28, 2024: This story was updated to include a comment from a Tessera spokesperson; remove the outdated information that Prime’s GSD1 program was moving to the clinic; and clarify the degrees of editing and cell types in Dr. Holmes’ presentation.
