CRISPR technology is rapidly advancing with promising clinical applications across a spectrum of diseases, from blood disorders to chronic infections and hereditary conditions. The field has achieved a significant milestone with the FDA's approval of the first CRISPR-based therapy, Casgevy (exagamglogene autotemcel), for sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). This approval has spurred further research and development, with numerous clinical trials underway to explore the potential of CRISPR in addressing unmet medical needs.
Advancements in Blood Disorders
Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, utilizes CRISPR-Cas9 to edit a gene and reactivate fetal hemoglobin production, effectively compensating for the defective red blood cells in SCD. Phase 3 trial data demonstrated that 16 out of 17 patients with SCD stopped experiencing vaso-occlusive crises, and 25 out of 27 patients with TDT became transfusion-independent. These results have been observed for over three years in some cases.
While Casgevy does not directly correct the mutations causing SCD and TDT, it provides long-term disease management. The treatment involves ex vivo editing techniques, requiring chemotherapy to prepare patients for the integration of genetically modified cells. CRISPR Therapeutics is exploring in vivo editing to reduce or eliminate the need for intensive chemotherapy.
Other companies are also pursuing CRISPR-based therapies for SCD. Editas Medicine is conducting phase 1/2 trials using Cas12a to activate fetal hemoglobin production, with early results showing clinical benefits without serious adverse events. Beam Therapeutics has initiated a phase 1/2 trial using base editing to enhance fetal hemoglobin without causing double-stranded DNA breaks, potentially minimizing safety risks.
Expanding Applications Beyond Blood Disorders
CRISPR's potential extends beyond blood disorders, with applications in treating urinary tract infections (UTIs). Locus Biosciences is recruiting participants for a phase 2/3 trial to address UTIs caused by antimicrobial-resistant Escherichia coli. Their therapy, LBP-EC01, is a cocktail of three bacteriophages with CRISPR-Cas3 that targets and destroys the genomes of common E. coli strains. This approach, which degrades DNA rather than repairing it, was first tested in a phase 1b trial in the US.
Intellia Therapeutics is also making strides in treating complex genetic diseases. Their drug, NTLA-2001, is the first CRISPR-Cas9 therapy administered in a lipid nanoparticle (LNP) for systemic delivery to treat hereditary transthyretin amyloidosis (hATTR). Clinical trials have shown a significant reduction in toxic protein levels, with over 85% reduction at the lowest dose and more than 90% at the highest dose. Intellia is now recruiting for a phase 3 trial to assess NTLA-2001 for cardiomyopathy.
NTLA-2002, another CRISPR-Cas9 drug from Intellia, targets hereditary angioedema (HAE) by targeting the KLKB1 gene. Early results from clinical trials have shown a significant decrease in the frequency of attacks, with the highest dosage achieving more than a 90% reduction in inflammatory protein levels. Intellia is planning a global phase 3 trial in 2024 to confirm these results.
Addressing Cardiovascular and Metabolic Diseases
CRISPR is also being explored for cardiovascular diseases and metabolic disorders like type 1 diabetes. Verve Therapeutics is progressing through a phase 1 trial with Verve-101, a gene editing treatment for familial hypercholesterolemia. Verve-101 uses base editing to modify the PCSK9 gene in the liver, aiming to reduce cholesterol levels. Early results have shown a significant reduction in low-density lipoprotein cholesterol.
CRISPR Therapeutics has initiated phase 1 trials targeting angiopoietin-like 3 protein and lipoprotein(a), which are linked to cardiovascular risks. In the realm of metabolic diseases, CRISPR Therapeutics, in partnership with ViaCyte, initiated a phase 1 trial targeting type 1 diabetes, employing CRISPR-Cas9 to modify pancreatic cells derived from stem cells to reduce immune system attack.
Autoimmune and Viral Diseases
CRISPR Therapeutics is also conducting a pre-clinical trial study using next-generation CD19-targeting chimeric antigen receptor (CAR) T cells for systemic lupus erythematosus (SLE). This marks the first use of CRISPR gene-editing technology for autoimmune diseases, adapting CAR T cells to target and temporarily deplete B cells.
For HIV, Excision Biotherapeutics is conducting a phase 1 clinical trial for an HIV treatment that uses CRISPR-Cas9 to excise key segments of the viral genome from infected cells. The CRISPR components are delivered via an adeno-associated virus 9 (AAV9) vector in a single infusion.
Challenges and Future Directions
Despite the promise of CRISPR technology, challenges remain. The high cost of therapies like Casgevy, priced at $2 million per patient, raises concerns about accessibility and affordability. Regulatory bodies also face the challenge of keeping pace with rapid advancements in gene therapy and establishing standards to manage potential off-target effects and ethical implications.
As research continues, the focus will be on addressing these challenges to ensure that gene editing is both effective and accessible across scientific and medical communities. The convergence of interdisciplinary collaborations and nanomaterial integration is expected to drive transformative discoveries and improve human health outcomes.
