By Alex Philippidis

NEW YORK—David R. Liu, PhD, the genome editing pioneer whose Broad Institute lab developed both base editing and prime editing technologies over the past decade, told an audience of investors that prime editing is on track to join base editing in human clinical trials in less than a year.

“Likely the first clinical trial will be in 2024,” Liu said, speaking via video at the Chardan 7^th Annual Genetic Medicines Conference, held this week in New York City. “Prime editors, we anticipate, will be in the clinic next year.”

Liu is a co-founder of Prime Medicine, the publicly traded company formed to commercialize prime editing by developing treatments based on applying the technology’s “search and replace” approach to genome editing.

In releasing second-quarter results in August, Prime Medicine conveyed the possibility of a first trial for its gene editing technology next year by publicly including among its anticipated upcoming milestones: “Complete first IND filing as early as 2024.” Additional IND filings are anticipated in 2025, Prime Medicine said in a company presentation to investors last month.

By contrast, base editing technology, first disclosed in 2016 by Liu’s lab—is under investigation in six ongoing clinical trials.

Prime Medicine has not yet released which of its 18 pipeline programs will be selected as its first clinical-phase candidate.

IND-enabling candidate

According to Prime Medicine’s presentation last month, only one of its programs has reached the phase of IND-enabling studies—a blood-targeting candidate for chronic granulomatous disease (CGD), designed to be administered ex vivo.

Three other programs are in lead optimization phases—a Wilson’s disease candidate targeting liver tissue and using lipid nanoparticle (LNP) delivery; a retinitis pigmentosa/rhodopsin candidate targeting eye tissue and using adeno-associated virus (AAV) vector delivery; and a neuromuscular tissue targeting candidate for Friedreich’s ataxia also delivered via AAV.

The rest of Prime Medicine’s pipeline programs are in preclinical discovery phases.

During the conference, Liu noted that AAV has fallen out of favor with some gene therapy developers, concerned about harm to patients from needed redosing, as that will often induce high-titer neutralizing antibodies that make it difficult for a second AAV dose to be effective. That’s less likely to be a problem in genome editing, Liu asserted, as long as the editing therapy is effective enough to be a one-time treatment.

“If you look at some of the new generation AAVs that have liver detargeting, that go to previously challenging organs like the brain or muscle or lung, even in primates in some cases, I actually think those AAVs are going to be powerful tools for the delivery of these gene editing agents, especially because we anticipate that we will only need to deliver them once to effect a permanent benefit for the patient,” Liu said.

Both prime and base editing are designed to engineer precise base substitutions while avoiding double-stranded DNA breaks (as occurs in CRISPR-Cas9 gene editing). As a postdoctoral fellow in Liu’s lab, Alexis Komor, PhD, spearheaded the development of the first base editing technology, which could install specific base substitutions (C to T or G to A) without cleaving DNA. Eighteen months later, her colleague Nicole Gaudelli, PhD, developed a complementary adenine (A to G) base editor. Both base editing approaches were detailed in separate papers published in Nature.

In 2019, Liu, former postdoc Andrew Anzalone MD, PhD, and colleagues detailed prime editing in Nature. In prime editing, the desired edit is supplied in an extension to the guide RNA, which is then converted to DNA using the enzyme reverse transcriptase. The technology can introduce targeted insertions, deletions, and all 12 possible base-to-base conversions.

Generating positive results

In May, Liu and colleagues published in Nature Biotechnology a paper entitled “Efficient prime editing in mouse brain, liver and heart with dual AAVs”, in which they sought to address bottlenecks limiting AAV-mediated prime editing in vivo by developing AAV-PE vectors with increased PE expression, stability of prime editing guide RNA, and modulation of DNA repair.

The study detailed how two dual-AAV systems were developed—v1em and v3em PE-AAV. They generated positive results by enabling therapeutically relevant levels of prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%).

The group declared that the results represented “the first prime editing in postnatal brain and heart and substantially higher AAV-mediated in vivo prime editing efficiencies than have been previously reported in the liver.”

The dual-AAV systems were also used to install the rare Apolipoprotein E Christchurch (APOE3 R136S) variant in vivo for Alzheimer’s disease in astrocytes, and the dominant variant of proprotein convertase subtilisin/kexin type 9 (PCSK9) Q152H (mouse Pcsk9 Q155H), associated with a reduction in low-density lipoprotein (LDL) cholesterol levels and protection from coronary artery disease in hepatocytes.

“Our results advance the potential of prime editing for basic research and therapeutic applications and establish optimized PE-AAV systems as an effective in vivo PE delivery method,” Liu and colleagues concluded in the study.

Correcting CGD mutation

Also in May, Prime Medicine researchers presented updated preclinical data showing the potential of prime edited cells to correct the causative mutation of chronic granulomatous disease (CGD) at the American Society of Gene and Cell Therapy (ASGCT) 26^th Annual Meeting, held in Los Angeles.

In an abstract, “Prime Editing of Human CD34+ Long-Term Hematopoietic Stem Cells Precisely Corrects the Causative Mutation of p47phox Chronic Granulomatous Disease and Restores NADPH Oxidase Activity in Myeloid Progeny,” the researchers reported greater than 90% prime editing in CD34⁺ cells from four donors—a finding they said showed their technology to be highly reproducible.

“These data show that prime editing precisely corrects the ΔGT mutation at NCF1 in p47phox CGD patient CD34+ cells and restores NADPH oxidase activity and myeloid cell function in progeny of these PE-corrected cells, thus representing a potential curative approach for p47phox CGD patients,” the Prime Medicine researchers concluded.

Earlier data showed the ability of prime editing to correct a CGD causative mutation in CD34⁺ cells ex vivo, with the prime edited CD34⁺ cells engrafting long-term in vivo and editing levels greater than 92%.

During the ASGCT conference—which featured a presidential symposium keynote address by Liu—Prime Medicine highlighted its Prime Editing Assisted Site-Specific Integrase Gene Editing (PASSIGE) platform, showcasing its potential application to generate multiplex-edited chimeric antigen receptor (CAR)-T cells for the treatment of some cancers and immune diseases, without the use of viruses.

Liu co-founded Prime Medicine with Anzalone, currently the company’s head of the prime editing platform. Anzalone detailed his creation of prime editing and career in genome editing earlier this year in an exclusive interview on GEN Edge’s video interview series “Close to the Edge”, and published in our sister journal GEN Biotechnology.

Genome editing methods

Base and prime editing, Liu told conferees, were two of three different ways that have emerged for editing the genomes of human cells currently that meet the criteria of reasonably efficient and reasonably specific, used by hundreds of laboratories, and well-validated. The third, he said, was using CRISPR nucleases, which can result in gene disruption and creation of indels.

There are three base-editing candidates now in clinical trials:

• BEAM-101: Beam Therapeutics—co-founded by Liu with Feng Zhang, PhD, and Keith Joung, MD—is assessing BEAM-101, delivered via autologous bone marrow transplant, to treat severe sickle cell disease in adults in the Phase I/II BEACON trial (NCT05456880). Beam said in August it had enough consented patients to fill its sentinel cohort and begin an expansion cohort. Beam expects to report initial patient data from BEACON in 2024.
• BEAM-201: Beam last month dosed the first patient in a Phase I/II trial (NCT05885464) evaluating BEAM-201, a multiplex base-edited CAR-T cell therapy for the treatment of relapsed/refractory T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LL).
• VERVE-101: Verve Therapeutics is studying VERV-101—the first in vivo base editing therapy to reach the clinic—to treat heterozygous familial hypercholesterolemia (HeFH) in the Phase Ib heart-1 trial (NCT05398029), enrolling patients in New Zealand and the U.K. Verve expects to complete patient enrollment outside the U.S. after the FDA placed a hold on its IND application pending additional data.

The progression of base and prime editing from research papers to preclinical to clinical trials have both been swift, Liu observed. “These are breathtakingly fast transitions from academia to actual clinical applications,” Liu said, paying tribute to numerous laboratories advancing these technologies. “There are, for example, more than 1,000 research papers published on base editors and prime editors,” he said.

“Our lab has not published most of those,” Liu quipped, drawing laughs. “And it’s something that has really helped establish the robustness of the technology, de-risk it, improve it, and given us and the patient communities some confidence that it can be deployed in ways that are useful for helping patients.”

Alex Philippidis is Senior Business Editor of GEN.

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