Adapted from a bacterial defense system into a programmable tool for editing DNA, CRISPR-Cas9 was described in a landmark 2012 Science paper by teams led by Jennifer Doudna and Emmanuelle Charpentier, work that won the 2020 Nobel Prize in Chemistry. Thirteen years on, the first CRISPR medicine is in patients, the first in-body edit has cleared its proof-of-concept in the New England Journal of Medicine, and the harder questions are no longer about whether it works but who can afford it.
CRISPR is a bacterial defense system, repurposed
CRISPR is a system bacteria use to remember and destroy the DNA of viruses that attack them. In the 2012 paper that opened the field, the authors wrote that they had shown a way to “propose an alternative methodology based on RNA-programmed Cas9 that could offer considerable potential for gene-targeting and genome-editing applications.” That understated line was the starting point for the field that followed.
The tool has two parts. A short strand of guide RNA carries the address of the target sequence. A protein called Cas9 acts as the scissors, cutting the DNA at that address. Once the cut is made, the cell’s own repair machinery finishes the job, either disabling the gene or, if a template is supplied, replacing it with a new sequence. The specificity comes from the guide RNA, which can be redesigned in software to point Cas9 at any DNA sequence a scientist chooses.
The first CRISPR medicine reached patients in December 2023
Casgevy (exagamglogene autotemcel), the first CRISPR-based therapy, was approved by the FDA in December 2023 for severe sickle cell disease. It was cleared five weeks later for transfusion-dependent beta thalassemia, a related inherited blood disorder. Both approvals rested on a striking pivotal trial result: 29 of 31 treated patients had no severe pain crises for at least 12 consecutive months over 24 months of follow-up (Frangoul et al., NEJM 2021).
Casgevy works outside the body, an approach known as ex vivo editing. A patient’s own bone marrow stem cells are collected, edited to reactivate fetal hemoglobin (a form the body normally shuts off after birth), and infused back. The revived fetal hemoglobin dilutes the mutant adult form and prevents the sickling that causes the disease.
Uptake has been slower than the enthusiasm around approval suggested. Vertex, Casgevy’s maker, reported that 147 patients globally had started the treatment process in 2025 and 64 had received their edited cells, a pattern that reflects both the complexity of the procedure and the price.
Editing inside the body cleared its first human test in 2025
Ex vivo editing works for blood cells, which can be taken out and put back. Most tissues cannot. The bigger prize is in vivo editing, changing genes inside the body itself. In 2025, that field passed its first serious test.
Verve Therapeutics reported the first published human proof-of-concept for in vivo base editing, a refined form of CRISPR that flips a single DNA letter without cutting both strands. The trial delivered a base editor by intravenous infusion to permanently switch off PCSK9, a gene that controls low-density lipoprotein (LDL) cholesterol. Mean LDL fell by 53%, with a maximum drop of 69%, from a single dose. The result, published in the New England Journal of Medicine in 2026 (Kathiresan et al.), is early phase 1 evidence, not a licensed treatment, but it turned a decades-old idea into working clinical data.
Base and prime editing sharpen the tool further
The original CRISPR-Cas9 system cuts both strands of the DNA helix and relies on the cell’s error-prone repair. Newer tools try to avoid the cut altogether. Base editing swaps one DNA letter for another. Prime editing writes short new sequences into a target location like a genetic word processor. Both promise fewer off-target changes, a persistent concern with first-generation CRISPR, and both are moving into clinical testing.
Cost is now the main barrier, not the science
Casgevy’s list price is $2.2 million per patient. Lyfgenia, a competing gene therapy from Bluebird approved on the same day, is $3.1 million. Neither figure includes the months of hospital conditioning, apheresis, and post-infusion monitoring that push the actual cost of care past $3 million. About 60% of sickle cell patients in the United States are covered by Medicaid, which is not built to absorb costs at that scale.
The federal response is the Cell and Gene Therapy Access Model, opened by the Centers for Medicare and Medicaid Services (CMS) in 2025. Under the model, 33 states and the District of Columbia have signed outcomes-based agreements: if the therapy does not deliver the specified clinical result for a given patient, the manufacturer pays a portion of the cost back. It is the first policy answer at national scale to a question every future gene therapy will raise.
What the evidence cannot yet answer
The technical worries have not disappeared. Edits at unintended sites in the genome remain the most closely watched safety signal, especially for the newer in vivo work where the editor circulates in the body. Immune responses to Cas9 are another concern, since the protein is bacterial and the human immune system can recognize it. And getting the editor to the right tissue efficiently is still hard: most in vivo programs so far target the liver, because lipid nanoparticles delivered intravenously naturally accumulate there. Reaching other organs will require new delivery systems, and until that is solved the class will stay narrower than its early promise.
References
- Jinek M, Chylinski K, Fonfara I, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 2012; 337: 816-821. DOI: 10.1126/science.1225829
- Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. New England Journal of Medicine, 2021; 384: 252-260. DOI: 10.1056/NEJMoa2031054
- Kathiresan S, Nissen SE, Cannon CP, et al. In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia. New England Journal of Medicine, 2026. DOI: 10.1056/NEJMoa2601283
- US Food and Drug Administration. FDA approves first gene therapies to treat patients with sickle cell disease. Press release, December 8, 2023. Available at: fda.gov
- Centers for Medicare and Medicaid Services. Cell and Gene Therapy Access Model. Available at: cms.gov