How big is the off-target editing problem?
The risk of off-target edits—where CRISPR cuts DNA at unintended locations—is a central long-term safety concern, and the evidence suggests it may be larger than many assume. A 2025 review of CRISPR therapeutics for human diseases emphasizes that substantial off-target genotoxicity remains a key barrier to clinical translation, and critically, there are no standardized guidelines for measuring or reporting these effects [1]. This means different studies use different methods to assess off-target activity, making it hard to compare risks across therapies and potentially allowing dangerous edits to go undetected.
The problem is compounded by the fact that CRISPR editors, whether delivered as DNA, RNA, or protein, lack natural tissue specificity. A 2023 study on delivery systems notes that these editors have poor membrane permeability and no built-in organ targeting, raising concerns about off-target editing at the tissue level—meaning the edit could occur in the wrong organ, causing unintended genotoxicity [2]. The same paper highlights that prolonged Cas9 activity further increases the risk of off-target genomic edits, as the enzyme remains active longer than necessary [2].
Have there been real-world safety failures?
Yes, and one case is particularly alarming. A 2023 report details the death of a Duchenne muscular dystrophy (DMD) patient following a clinical trial that used CRISPR transactivation delivered by an adeno-associated virus (AAV) vector [4]. This is a concrete, tragic example that the risks are not theoretical—they can be fatal. The paper explicitly states that this event has "cast a spotlight on the potential risks associated with these approaches" [4]. While the exact cause of death is not detailed in the abstract, the fact that a patient died in a trial underscores that long-term safety profiles are still poorly understood.
Beyond this case, broader safety concerns are echoed across the literature. A 2024 review of CRISPR therapy notes that despite the 2023 approval of CRISPR-Cas9 for sickle cell anemia, challenges like long-term security and efficient delivery remain unresolved [5]. The same review points out that off-target mutations and the need for precise dosage control are critical hurdles, and tools to predict unwanted mutations (like CasOT) are still being developed [5]. This suggests that even approved therapies may carry unknown long-term risks.
Why do delivery challenges make long-term risks worse?
The way CRISPR is delivered into the body directly affects its long-term safety, and current methods have significant shortcomings. A 2026 review focused on CRISPR for Alzheimer's disease highlights that crossing the blood-brain barrier (BBB) is the most significant challenge for clinical translation, and that delivery inefficiency can lead to incomplete editing or off-target effects [3]. The same paper notes that the Cas nuclease protein itself can trigger an immune response (immunogenicity), which could cause inflammation or other long-term complications [3].
These delivery problems are not unique to the brain. A 2023 study on delivery systems explains that even when CRISPR reaches the right tissue, the editors often fail to enter cells efficiently, and the lack of tissue specificity means that editing can occur in unintended organs [2]. This combination—poor targeting and potential immune reactions—means that long-term risks like chronic inflammation, immune rejection, or edits in stem cells (which could be passed on) are not being adequately addressed in current trials.
About These Sources
This answer is built on 5 peer-reviewed studies — published from 2023 to 2026, 3 from 2024 or later, 3 in Q1 journals, collectively cited 66 times — selected as the most relevant from 5 studies that passed quality screening, drawn from 67 papers retrieved from a database of over 500 million.
Sources used in this answer
Off-target effects in CRISPR-Cas genome editing for human therapeutics: Progress and challenges
This 2025 review identifies off-target genotoxicity as a major barrier to clinical translation of CRISPR therapies and notes the absence of standardized guidelines for measuring off-target effects, leading to inconsistent safety assessments across studies.
Development of CRISPR/Cas Delivery Systems for In Vivo Precision Genome Editing
This 2023 study on delivery systems reports that CRISPR editors lack tissue specificity and have poor membrane permeability, and that prolonged Cas9 activity increases off-target genomic editing risk, emphasizing the need for molecular switches to control activity.
CRISPR-based correction of apolipoprotein E4 in Alzheimer's disease: Therapeutic strategies and macromolecular delivery innovations.
This 2026 review on CRISPR for Alzheimer's disease identifies crossing the blood-brain barrier as the most significant clinical challenge and highlights concerns about Cas nuclease immunogenicity and long-term genomic safety.
Safety concerns surrounding AAV and CRISPR therapies in neuromuscular treatment
This 2023 report describes the death of a Duchenne muscular dystrophy patient following a trial using CRISPR transactivation with AAV vectors, underscoring real-world fatal risks associated with these therapies.
CRISPR therapy: A revolutionary breakthrough in genetic medicine
This 2024 review notes that despite the 2023 approval of CRISPR for sickle cell anemia, challenges including long-term security, off-target mutations, and efficient delivery remain unresolved.