The CRISPR medicine landscape is rapidly evolving, marked by the first-ever approval of a CRISPR-based therapy, Casgevy, for sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). This milestone, achieved in late 2023, signals a new era in genome editing, yet the field faces significant financial and regulatory hurdles. "Going from the lab to an approved CRISPR therapy in just 11 years is a truly remarkable achievement," says IGI Founder Jennifer Doudna. "I am especially pleased that the first CRISPR therapy helps patients with sickle cell disease, a disease that has long been neglected by the medical establishment. This is a win for medicine and for health equity."
Financial and Market Pressures
Despite the enthusiasm, market forces have reduced venture capital investment in biotechnology. Companies are hyper-focused on clinical trials to quickly bring new products to market, leading to layoffs and a narrowing of focus on late-stage products. This year, a trial in autoimmunity represents the only new disease area being explored, highlighting the impact of financial constraints on expanding the pipeline.
Blood Disorders: SCD and TDT
Casgevy, developed by CRISPR Therapeutics and Vertex, induces the expression of fetal hemoglobin (HbF) to compensate for the missing healthy adult hemoglobin in SCD and TDT patients. Data from a phase 3 trial showed that 25 of 27 individuals with TDT were no longer transfusion dependent, and 16 of 17 SCD patients were free of vaso-occlusive crises. Increases in fetal hemoglobin occurred within the first few months and were maintained over time.
Editas Medicine is also conducting phase 1/2 trials using a CRISPR system with a Cas12a protein. Early results show similar efficacy to Casgevy, with all SCD patients (11) showing robust increases in fetal hemoglobin levels and freedom from vaso-occlusive events. In January 2024, Beam Therapeutics announced dosing the first participant in a phase 1/2 trial of a base editing therapy for severe SCD.
Improving CRISPR Treatments for SCD & TDT
CRISPR Therapeutics and Beam are pursuing strategies for in vivo editing for SCD and TDT. "There is no doubt in my mind that in a decade we will move editing outside of the realm of the bone marrow transplantation unit and into a setting where the patient gets an IV injection. The path lies through the formidable obstacle of the risks of having something untoward happen," says Urnov. Both companies are also investigating reducing the burden of chemotherapy conditioning by targeting the chemotherapy to specific cells with antibodies, ultimately allowing the use of lower doses.
Chronic Bacterial Infection: Urinary Tract Infections (UTIs)
A cocktail of three bacteriophages combined with CRISPR-Cas3 is in clinical trials to treat chronic UTIs. Locus Biosciences completed their US-based Phase 1b trial in February 2021, with initial results showing a decrease in the level of E. coli in the bladder of participants given the CRISPR-based treatment. Locus began enrolling participants for a phase 2/3 trial in 2022, planning to enroll approximately 800 participants from the US and European Union.
Protein-Folding Disease: Hereditary Transthyretin Amyloidosis (hATTR)
Intellia Therapeutics is conducting a trial for hATTR, a fatal disease caused by mutations in the TTR gene. The treatment uses CRISPR-Cas9 tools to reduce the amount of faulty TTR protein the body makes. Even at the lowest treatment dose, there is a deep (>85%) reduction in the amount of toxic protein in the participants’ blood streams, with greater than 90% reduction for participants receiving the highest dose. Intellia has gotten FDA approval to move forward with a phase 3 study of NTLA-2001.
Inflammatory Disease: Hereditary Angioedema (HAE)
Intellia Therapeutics is also trialing a treatment for HAE using CRISPR-Cas9 tools to reduce the amount of an inflammatory protein the body makes. Early-stage trials have shown encouraging results, with most participants free from attacks in the interval between treatment and their most recent follow-up. Intellia plans to initiate a global phase 3 trial later this year.
Cancers: CAR-T Immunotherapy
Researchers are using CRISPR to enhance CAR-T immunotherapy. CRISPR Therapeutics is testing next-generation allogeneic CRISPR-modified CAR-T cells in phase 1/2 clinical trials. Caribou Biosciences is testing CAR-T cells with a second genetic modification: knockout of PD-1. In a US-based phase 1 trial of 16 participants, 15 responded to the treatment, with seven of 16 (44%) having a complete remission lasting six months or longer. Beam Therapeutics reported dosing the first patient in their phase 1/2 of an anti-CD7 CAR-T treatment for T cell leukemia and lymphoma.
Cardiovascular Disease
Verve Therapeutics began their trial for familial hypercholesterolemia using a base editor delivered by lipid nanoparticle (LNP). The two participants given the middle dose saw a 39% and 48% reduction in LDL cholesterol, respectively, while the participant given the highest dose saw a 55% reduction. Verve got the green light to resume the trial in the US in October 2023. In 2023, CRISPR Therapeutics initiated two phase 1 trials for additional targets for cardiovascular disease, targeting angiopoietin-like 3 protein (ANGPTL3) and lipoprotein(a) (Lp(a)).
HIV/AIDS
Excision Biotherapeutics is conducting a phase 1 trial using CRISPR to target the HIV DNA sequence stored in the host cell genome. As of October 2023, there were no reports of significant severe adverse effects.
Diabetes
CRISPR Therapeutics and ViaCyte initiated a phase 1 trial using CRISPR to edit the immune-related genes of pancreatic cells made from stem cells. The intellectual property rights have since been fully transferred to CRISPR Therapeutics and they intend to continue the phase 1 trial.
Autoimmune Disease
CRISPR Therapeutics is initiating a trial treating patients with SLE with their next-generation CD19-targeting CAR-T cells. This will be the first application of CRISPR to the autoimmune space.
Outlook
As CRISPR clinical trials expand, novel regulatory approaches are needed to fully realize the therapeutic potential of CRISPR, especially for rare diseases. "The vision is that going from treating one condition to another will be much faster, cheaper, and more scalable than going back to square one," says Urnov.
