The successor to CRISPR: what comes next in gene editing

01CRISPR's achievements and limitations

CRISPR gene editing is a genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. It is based on a simplified version of the bacterial CRISPR-Cas9 antiviral defense system. By delivering the Cas9 nuclease complexed with a synthetic guide RNA (gRNA) into a cell, the cell's genome can be cut at a desired location, allowing existing genes to be removed or new ones added. Since its development in 2012, CRISPR has been used in thousands of laboratories worldwide and has led to approved therapies, including the sickle cell disease treatment Casgevy, approved by the FDA in December 2023.

Despite its transformative impact, CRISPR-Cas9 has significant limitations. The system creates double-strand breaks in DNA, which can trigger unintended chromosomal rearrangements and large deletions. The repair pathway used by the cell — typically non-homologous end joining (NHEJ) — is error-prone and can introduce random insertions or deletions at the cut site. Additionally, CRISPR relies on a protospacer adjacent motif (PAM) sequence near the target site, limiting where edits can be made. Off-target effects, where Cas9 cuts at unintended genomic locations, remain a persistent safety concern for clinical applications.

02Prime editing and base editing explained

Prime editing is a "search-and-replace" genome editing technology that directly writes new genetic information into a targeted DNA site without creating double-strand breaks. Developed by the Liu Lab at Broad Institute in 2019, the most basic prime editor uses a fusion protein consisting of a catalytically-impaired programmable endonuclease linked to an engineered reverse transcriptase, and a prime editing guide RNA (pegRNA) capable of identifying the target site and providing the new genetic information. This approach can install all 12 types of point mutations, as well as small insertions and deletions, with far fewer off-target effects than CRISPR-Cas9.

Base editing, developed by the same lab in 2016, takes a different approach. Instead of cutting DNA, base editors chemically convert one DNA base into another without breaking the DNA backbone. Cytosine base editors (CBEs) convert C·G to T·A, while adenine base editors (ABEs) convert A·T to G·C. Together, these cover the majority of disease-causing point mutations. Base editing has already entered clinical trials for sickle cell disease and high cholesterol, with early results showing durable edits after a single treatment.

03Epigenome editing: a new approach

Rather than changing the DNA sequence itself, epigenome editing modifies how genes are expressed without altering the underlying genetic code. This is achieved by fusing deactivated Cas9 (dCas9) with enzymes that add or remove epigenetic marks such as DNA methylation or histone modifications. By targeting these epigenetic regulators to specific genomic loci, researchers can silence or activate genes reversibly.

The appeal of epigenome editing is its reversibility — if an edit causes problems, it can potentially be undone, unlike permanent DNA changes. Research published in 2021 demonstrated targeted DNA methylation editing in animal models, and the technology has shown promise for treating conditions where gene expression is dysregulated, including certain cancers and neurological disorders. However, the field is still in its early stages, and the long-term stability of epigenetic edits in dividing cells remains an open question.

04Off-target effects and safety improvements

Safety is the paramount concern for any gene editing technology intended for human use. CRISPR-Cas9's off-target effects have been extensively studied, and researchers have developed high-fidelity Cas9 variants with reduced off-target activity. Whole-genome sequencing of edited cells has become standard practice in clinical development pipelines. Prime editing and base editing both fundamentally reduce the risk of off-target effects by avoiding double-strand breaks, but they introduce their own challenges — prime editors are less efficient than CRISPR at some target sites, and base editors can cause bystander edits near the target site.

Newer delivery methods also improve safety. Lipid nanoparticle delivery, used in mRNA vaccines, can transiently deliver editing machinery without viral integration risk. Ex vivo editing — where cells are removed, edited, and returned to the patient — allows quality control before treatment. The FDA approval of Casgevy demonstrated that ex vivo CRISPR editing can meet regulatory standards, but in vivo delivery to specific tissues remains a challenge.

05Clinical trials using next-gen gene editing

The clinical pipeline for next-generation gene editing is expanding rapidly. Vertex Pharmaceuticals' Casgevy, the first CRISPR-based therapy approved by the FDA, treats sickle cell disease and beta-thalassemia by editing hematopoietic stem cells ex vivo. Verve Therapeutics is conducting trials of base editing for familial hypercholesterolemia, aiming to permanently lower LDL cholesterol with a single injection — an approach that could replace lifelong statin use. Beam Therapeutics has multiple base editing programs in development targeting sickle cell disease, alpha-1 antitrypsin deficiency, and glycogen storage disease.

Prime editing trials are earlier in development but moving forward. Prime Medicine, co-founded by prime editing inventor David Liu, initiated its first clinical program for chronic granulomatous disease in 2024. The broader landscape includes dozens of preclinical programs targeting genetic liver diseases, eye disorders, and immune cell engineering for cancer therapy. The total number of active gene editing clinical trials has grown from fewer than 10 in 2020 to over 60 across all modalities by 2025.

06The ethics of heritable gene editing

Heritable gene editing — modifying embryos, eggs, or sperm so that changes are passed to future generations — remains one of the most contentious issues in biotechnology. The 2018 announcement that Chinese scientist He Jiankui had created the first CRISPR-edited babies prompted international condemnation and led to a moratorium on heritable editing in most jurisdictions. The World Health Organization published recommendations in 2021 calling for a global registry of human genome editing research and stronger governance frameworks.

The case for heritable editing rests on eliminating devastating genetic diseases before birth, but critics argue it could lead to eugenics, exacerbate inequality, and introduce unforeseeable consequences into the human gene pool. Somatic gene editing, which only affects the treated individual, is broadly considered ethically acceptable and is the focus of current clinical trials. The distinction between therapeutic and enhancement applications remains legally and ethically unresolved in most countries, and regulatory frameworks have not kept pace with technological advances.

07Commercialization and access challenges

The commercialization of gene editing therapies faces significant access challenges. Casgevy costs approximately $2.2 million per patient, making it one of the most expensive therapies ever approved. The treatment requires specialized medical facilities, weeks of hospitalization, and a complex ex vivo editing process that limits scalability. Insurance coverage decisions are still being made, and the infrastructure to deliver such therapies to the patients who need them most — many of whom live in low- and middle-income countries — does not yet exist.

Intellectual property disputes have also shaped the commercial landscape. The Broad Institute and UC Berkeley engaged in a decade-long patent battle over CRISPR-Cas9, with broad implications for licensing and royalties. Prime editing and base editing are covered by separate patent portfolios, primarily controlled by Broad Institute and its licensees. The concentration of IP rights in a small number of institutions and companies raises questions about whether these technologies will be accessible to researchers and patients globally, or whether they will follow the pattern of previous biotech breakthroughs where access is determined by wealth.