CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a gene-editing technology that precisely modifies DNA. It holds promise for addressing genetic diseases. The “therapeutics pipeline” describes the progression of potential treatments from initial discovery through development stages, aiming for clinical application. This illustrates the journey of CRISPR-based interventions from laboratory research toward becoming available medical treatments.
How CRISPR Gene Editing Works
CRISPR-Cas9 functions as a molecular scissor, cutting DNA at specific locations. This system relies on two main components: a guide RNA (gRNA) and the Cas9 enzyme. The gRNA matches a DNA sequence, directing the Cas9 enzyme to the target site. Once at the target, the Cas9 enzyme creates a double-stranded break in the DNA.
The cell’s natural repair mechanisms fix this break. Scientists can manipulate these repair pathways to achieve desired genetic changes. For instance, the non-homologous end joining (NHEJ) pathway can disable a gene, a process known as gene “knockout.” Alternatively, the homology-directed repair (HDR) pathway can insert new genetic material or correct a faulty gene, a process called gene “knock-in.”
Diseases Targeted by CRISPR Therapies
CRISPR therapies target a range of genetic diseases. Hemoglobinopathies, like sickle cell disease (SCD) and beta-thalassemia, are targets where CRISPR aims to edit hematopoietic stem cells to produce fetal hemoglobin, correcting the underlying genetic defect.
In oncology, CRISPR is explored for cell therapies for various cancers, including solid tumors and hematologic malignancies. This involves modifying immune cells, like T cells, to enhance their ability to attack cancer cells. Inherited eye diseases and neurological conditions are also under investigation, with CRISPR aiming to correct gene mutations causing these disorders. Research also extends to cardiovascular diseases and autoimmune conditions, where CRISPR could reduce harmful protein expression or modify immune responses.
CRISPR Therapies in Clinical Trials
CRISPR therapies undergo clinical trials to assess safety and efficacy. Phase 1 trials evaluate safety in a small group. Phase 2 studies assess efficacy and safety in a larger group. Phase 3 trials compare the new treatment to existing ones in even larger patient populations.
As of February 2025, over 150 active clinical trials are evaluating gene-editing therapeutic candidates across various disease areas. The first CRISPR-based therapy, exagamglogene autotemcel (Casgevy), was approved for sickle cell disease and transfusion-dependent beta-thalassemia in late 2023. This therapy involves editing a patient’s blood stem cells to produce healthy hemoglobin.
Beyond hemoglobinopathies, other therapies are progressing. For instance, NTLA-2001 from Intellia Therapeutics and Regeneron Pharmaceuticals, a candidate for familial amyloid cardiomyopathy, is in a Phase 3 trial. This therapy inhibits transthyretin gene expression using lipid nanoparticle delivery. CRISPR Therapeutics also has pipeline candidates like CTX112 in oncology and autoimmune diseases, and CTX310 and CTX320 for cardiovascular indications, with updates expected in 2025.
Overcoming Development Challenges
Bringing CRISPR therapies to widespread use involves addressing scientific and practical challenges. A primary hurdle is the efficient and safe delivery of CRISPR components to specific target cells. Viral vectors, such as adeno-associated viruses (AAVs), are commonly used for delivery due to their high efficiency, but they can sometimes trigger immune responses or have limitations in terms of the size of the genetic material they can carry.
Another concern is off-target edits, which are unintended changes to DNA at locations other than the intended target. Researchers are developing strategies to enhance the specificity of Cas enzymes and improve delivery methods, including non-viral approaches like lipid nanoparticles (LNPs), to mitigate these risks. The body’s immune response to bacterial Cas proteins also poses a challenge, with studies showing pre-existing immunity in a portion of the population.
Future Directions and New Applications
CRISPR technology is expanding beyond its initial applications, with research exploring novel gene-editing tools. Base editing and prime editing represent advancements that allow for even more precise modifications to DNA without creating double-stranded breaks. Base editing enables the direct conversion of one DNA base pair to another, while prime editing offers the versatility to make various edits, including small insertions, deletions, and all 12 types of point mutations.
These refined techniques hold promise for correcting a broader range of genetic variants associated with human diseases. Emerging applications also include using CRISPR for broader purposes like controlling disease vectors through gene drives, or developing “smart” cells that can produce drugs within the body. The long-term vision for CRISPR involves its integration into personalized medicine, where treatments can be tailored to an individual’s unique genetic makeup.