What has already worked in humans?
The most advanced in vivo CRISPR therapy in humans targets hereditary angioedema, a rare genetic disease causing severe swelling attacks. In a phase 1 trial of 10 patients, a single dose of NTLA-2002 (a CRISPR-Cas9 therapy delivered via lipid nanoparticles) reduced the number of monthly attacks by an average of 95% across all dose levels, with no serious adverse events [1]. This is the first published human trial showing that a one-time in vivo CRISPR injection can durably treat a genetic disease.
Another human study targeted herpes simplex virus in the eye. Three patients with severe herpes stromal keratitis received a single injection of a CRISPR formulation into the cornea during corneal transplant surgery. Over an average of 18 months of follow-up, the virus remained undetectable, and no off-target edits or systemic side effects were found [12]. This shows in vivo CRISPR can be safe and effective for localized viral infections, though the sample is tiny.
The FDA has already approved one CRISPR-based therapy, Casgevy, for sickle cell disease in 2023, but that is an ex vivo therapy (cells edited outside the body) [14]. The in vivo approach—editing cells inside the body—is still in earlier stages, with only a handful of patients treated so far.
What are the biggest remaining hurdles?
Delivery is the number one challenge. CRISPR components must reach the right cells in the body without being degraded, causing immune reactions, or editing the wrong genes. Lipid nanoparticles (LNPs) and adeno-associated viruses (AAVs) are the main delivery vehicles, but each has drawbacks: AAVs can trigger immune responses and cause liver toxicity at high doses, while LNPs may not efficiently reach all target tissues [8][11]. A quantitative systems pharmacology model showed that the rate of LNP internalization in humans is about 5 times slower than in non-human primates, meaning human dosing may need to be higher or more frequent [4].
Immunogenicity is another major concern. The Cas9 protein itself, the delivery vehicle, and even the edited cells can trigger an immune response that reduces efficacy or causes side effects. A review of CRISPR therapeutics notes that adverse events from immunogenicity have been a major setback in gene therapy, and specific FDA recommendations now exist to address this [13]. The phase 1 angioedema trial did report infusion-related reactions and fatigue, but no severe immune events [1].
Off-target editing—where CRISPR cuts the genome at unintended sites—remains a risk, though newer tools like base editors (which change a single DNA letter without cutting both strands) are more precise. In the monkey study using base editors to target PCSK9, the edits were stable for 8 months with no reported off-target effects [7]. However, comprehensive long-term safety data in humans is still lacking [14].
Where is the field heading next?
The next wave of in vivo CRISPR therapies is targeting common diseases like high cholesterol. VERVE-201, a CRISPR base editing therapy that inactivates the ANGPTL3 gene, has shown in monkeys that a single dose can reduce circulating ANGPTL3 by 96% for over 600 days [2]. A similar approach targeting PCSK9 in monkeys lowered LDL cholesterol by about 60% for at least 8 months [7]. These are both 'once-and-done' treatments for cardiovascular disease, which affects millions of people.
Cancer is another major frontier. In vivo CRISPR is being used to engineer CAR-T cells directly inside the body, or to identify new drug targets. For example, a CRISPR screen in mice with glioblastoma identified four new druggable targets that could make immunotherapy more effective [9][10]. Another study used a focused CRISPR library to find that knocking out REGNASE-1, SOCS1, PTPN2, or P16INK4A improved CAR-T cell persistence in solid tumors, while other edits (like MED12) actually made things worse [5]. This shows that context matters—what works in one cancer type may not work in another.
A first-in-human phase 1 trial of Senza5 CART5, a CRISPR-edited CAR-T therapy for T-cell lymphoma, is now enrolling patients [3]. This therapy uses CRISPR to delete CD5 from both the CAR-T cells and healthy T cells to prevent fratricide (cells killing each other). The trial will test safety and efficacy in up to 30 patients. If successful, it would be one of the first in vivo CRISPR-edited cell therapies for cancer.
About These Sources
This answer is built on 14 peer-reviewed studies — published from 2021 to 2026, 9 from 2024 or later, 10 in Q1 journals, collectively cited 1,258 times — selected as the most relevant from 15 studies that passed quality screening, drawn from 73 papers retrieved from a database of over 500 million.
Sources used in this answer
CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.
In a phase 1 trial of 10 patients with hereditary angioedema, a single dose of NTLA-2002 (CRISPR-Cas9 targeting KLKB1) reduced monthly swelling attacks by an average of 95% with no severe adverse events.
An in vivo CRISPR base editing therapy to inactivate the ANGPTL3 gene: nomination of a development candidate for VERVE-201
Preclinical data for VERVE-201, a CRISPR base editor targeting ANGPTL3, showed a 96% reduction in circulating ANGPTL3 in monkeys for over 600 days after a single dose, and 88-89% reduction in a monkey model of homozygous familial hypercholesterolemia.
CD5-deleted chimeric antigen receptor cells (Senza5 CART5) to enhance immunotherapy against T-cell non-Hodgkin lymphoma: A first-in-human phase I clinical trial (NCT06420089).
A phase 1 trial (NCT06420089) is testing Senza5 CART5, a CRISPR-edited CAR-T therapy for T-cell lymphoma, using CD5 knockout to prevent fratricide; enrollment has begun.
A quantitative systems pharmacology (QSP) platform for preclinical to clinical translation of in-vivo CRISPR-Cas therapy
A quantitative systems pharmacology model predicted that the rate of LNP internalization in humans is about 5 times slower than in non-human primates, which affects dosing for in vivo CRISPR therapies.
An in vivo CRISPR screen unveils promising target genes to improve CAR-T cell efficacy in a solid tumor model.
An in vivo CRISPR screen in mice identified REGNASE-1, SOCS1, PTPN2, and P16INK4A as the most robust targets to improve CAR-T cell persistence in solid tumors, while MED12, PRDM1, and BATF knockout were detrimental.
Revolutionizing in vivo therapy with CRISPR/Cas genome editing: breakthroughs, opportunities and challenges
A review of in vivo CRISPR/Cas therapy highlights that enhanced specificity and minimizing off-target effects are crucial before full clinical translation, especially for cancer.
In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
In cynomolgus monkeys, a single infusion of lipid nanoparticles delivering CRISPR base editors targeting PCSK9 reduced LDL cholesterol by about 60% and PCSK9 by about 90%, stable for at least 8 months.
Viral and nonviral nanocarriers for in vivo CRISPR-based gene editing
A review of viral and nonviral nanocarriers for in vivo CRISPR delivery notes that AAVs and LNPs are most promising but face challenges with immunogenicity, liver toxicity, and off-target effects.
EXTH-16. UNBIASED DISCOVERY OF SYNERGISTIC VULNERABILITIES AGAINST GLIOBLASTOMA: AN INNOVATIVE<i>IN VIVO</i> CRISPR PROFILING PLATFORM TO UNLEASH THE POWER OF TUMOR-TARGETED CYTOKINE THERAPY
An in vivo CRISPR screen in a glioblastoma mouse model identified four novel druggable targets that synergize with L19-TNF immunotherapy, now in preclinical testing.
P12.19.A UNVEILING SYNERGISTIC STRATEGIES: CRISPR-GUIDED OPTIMIZATION OF L19-TNF IMMUNOCYTOKINE THERAPY IN GLIOBLASTOMA
A separate report on the same glioblastoma CRISPR screen confirms the identification of four synergistic drugs for L19-TNF immunotherapy, with preclinical evaluation ongoing.
Delivery of CRISPR-Cas tools for in vivo genome editing therapy: Trends and challenges
A review of delivery systems for in vivo CRISPR editing highlights that AAVs cause immunogenicity and liver toxicity, while VLPs and LNPs are emerging as safer alternatives.
In Vivo CRISPR Gene Editing in Patients with Herpes Stromal Keratitis
In three patients with herpes stromal keratitis, a single corneal injection of CRISPR targeting HSV-1 kept the virus undetectable for 18 months with no off-target edits or systemic adverse events.
Immunogenicity of CRISPR therapeutics—Critical considerations for clinical translation
A review of immunogenicity of CRISPR therapeutics notes that adverse immune reactions are a major roadblock to clinical translation, and FDA recommendations now address this.
CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.
A 2025 review states that the FDA approved the first CRISPR-based therapy (Casgevy) for sickle cell disease in 2023, but in vivo CRISPR therapies still face challenges with off-target effects, delivery, and immune responses.