10 Ways CRISPR Advancements Are Reshaping Healthcare

Gene Therapy

CRISPR-Cas9 — adapted from a naturally occurring genome editing system that bacteria use as an immune defense — is being explored for gene therapy to treat genetic disorders by correcting or modifying specific genes responsible for diseases such as cystic fibrosis or sickle cell anemia. On December 8, 2023, the United States Food and Drug Administration (FDA) approved the first CRISPR treatment for sickle cell disease, CASGEVY [exagamglogene autotemcel (exa-cel)].

CASGEVY, developed by Vertex and CRISPR Therapeutics, modifies a gene responsible for the shape and function of red blood cells and demonstrates a functional disease cure for a minimum of one year. With the FDA's approval, the US became the second country, after the United Kingdom's approval a month earlier, to authorize a CRISPR therapy for sickle cell disease.

Cancer Treatment

CRISPR is being utilized in cancer research to develop therapies that target and edit cancer-related genes, potentially providing more targeted and personalized treatment options.

In November 2022, CRISPR Therapeutics released initial findings from a trial involving allogeneic CD70-targeting CAR-T cells. The trial focused on individuals with kidney tumors that were unresponsive to conventional treatments. The therapy demonstrated favorable tolerability, lacking severe side effects, and achieved a disease control rate of 77%. One participant exhibited no evidence of the disease in the most recent update.

CRISPR Therapeutics is currently working on an updated version of the therapy that includes modifications targeting additional genomic sites.

HIV/AIDS Cure Research

Researchers are currently exploring the application of CRISPR technology to modify the DNA of human cells, rendering them resistant to human immunodeficiency virus (HIV) infection. This breakthrough represents a promising avenue toward achieving a functional cure for HIV/AIDS.

In 2023, Excision Bio's EBT-101 therapy for HIV received fast-track status from the FDA. This in vivo gene therapy utilizes a CRISPR-Cas9 dual-sgRNA system delivered through an adeno-associated virus (AAV). This non-enveloped virus can be engineered to deliver DNA to target cells. This therapy aims to remove the integrated retrovirus from the genome of human cells, offering a promising approach to combat HIV.

Inherited Diseases Prevention

CRISPR can prevent the inheritance of certain genetic diseases, such as cystic fibrosis, by editing the germline cells, affecting the genes passed on to future generations.

For example, cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which CRISPR-Cas9 can target and modify. By introducing a corrected DNA sequence, CRISPR could potentially restore the normal function of the CFTR gene, leading to the prevention or amelioration of cystic fibrosis.

Vertex has developed six approved medications designed explicitly for cystic fibrosis treatment; nevertheless, only four have received approval in the United States — TRIKAFTA, SYMDEKO, ORKAMBI, and KALYDECO. None of these pharmaceuticals currently utilize CRISPR technology. Instead, they belong to the cystic fibrosis transmembrane conductance regulator (CFTR) modulators category.

Antibiotic-Resistant Bacteria Control

CRISPR technology is being investigated to address the issue of antibiotic-resistant bacteria by selectively targeting and eradicating detrimental bacterial strains. The CRISPR-Cas system has evolved into a novel gene-editing tool that holds promise for preventing and managing bacterial drug resistance by precisely identifying and cutting DNA sequences that encode antibiotic-resistance genes. Utilizing CRISPR-Cas has the potential to play a crucial role in managing horizontal gene transfer and mitigating the dissemination of antibiotic resistance.

Rare Diseases Treatment

CRISPR is being investigated for treating rare genetic disorders by correcting mutations responsible for rare conditions. Although many trials for rare diseases using CRISPR-based engineering tools are still in their early stages, various strategies and examples of CRISPR-based approaches are being extensively explored.

One example of a CRISPR treatment being researched for a rare disease is the use of CRISPR to correct mutations in the gene responsible for Duchenne muscular dystrophy (DMD). Duchenne muscular dystrophy, caused by mutations in the dystrophin gene, is a rare genetic disorder characterized by progressive weakening and loss of muscle function.

Researchers are investigating the possibility of using CRISPR to correct the specific genetic mutations in the dystrophin gene that lead to DMD. By precisely editing the mutated gene, the aim is to restore the production of functional dystrophin protein, which is essential for maintaining muscle integrity. This approach holds the potential to halt or slow down the progression of the disease and improve the quality of life for individuals with DMD.

Organ Transplantation

One application of CRISPR in xenotransplantation is the modification of donor animals to reduce the risk of immune rejection. Using CRISPR, scientists can target and modify specific genes in the genomes of donor animals, such as pigs, which are often considered a potential source of organ transplantation. The aim is to introduce genetic modifications that minimize the expression of certain antigens recognized by the human immune system, thereby decreasing the likelihood of immune rejection upon transplantation.

CRISPR gene-editing technology was utilized in the University of Maryland School of Medicine's historic pig heart transplant in a groundbreaking medical breakthrough. This pioneering procedure aimed to reduce the risk of immune rejection by modifying specific genes in donor pigs, making them more compatible with the human immune system. The patient, Lawrence Faucette, 58, suffering from end-stage cardiovascular disease, became the world's second recipient of a pig heart transplant.

Unfortunately, Faucette passed away six weeks after the transplant on October 30, 2023, underscoring the complexity and challenges associated with xenotransplantation. While the patient's life post-transplant was relatively short, the successful use of CRISPR in this revolutionary procedure marks a significant stride in advancing the possibilities of organ transplantation and warrants further exploration in the ongoing quest to address organ shortages.

Neurodegenerative Diseases Research

CRISPR is also used to create cellular and animal models for studying neurodegenerative diseases like Alzheimer's and Parkinson's, aiding in developing potential therapies.

For example, a 2022 study showed that using the CRISPR-Cas9 system to delete the A53T-SNCA gene significantly improved conditions related to Parkinson's disease, such as the overproduction of α-synuclein, reactive microgliosis, dopaminergic neurodegeneration, and motor symptoms associated with the disease.

Malaria Prevention

CRISPR gene-editing technology is revolutionizing malaria prevention by targeting both the Plasmodium parasites responsible for the disease and the mosquitoes that transmit it. Scientists have successfully used CRISPR-Cas9 to edit the genome of Plasmodium falciparum, introducing genetic modifications associated with drug resistance and disrupting essential genes. CRISPR has been employed in mosquitoes to integrate antiparasite effector genes, making them incapable of transmitting the malaria parasite.

Researchers have also generated malaria-resistant mosquitoes by modifying specific genes like FREP1 in Anopheles gambiae mosquitoes. CRISPR-Cas9 has also been utilized to investigate gene function throughout the malaria parasite's life cycle, shedding light on key developmental stages. Furthermore, the technology has been instrumental in identifying antimalarial compounds and understanding their mechanisms of action.

In addition to malaria, CRISPR technology could be used to create genetically engineered mosquitoes that are resistant to infection by the Zika virus.

Enhanced Drug Discovery

This innovative gene-editing technology has opened new avenues for drug discovery by enabling researchers to perform CRISPR screens, which involve introducing perturbations (such as CRISPR knockout or base editing) and challenges (such as drugs) to cells. Pooled CRISPR screens have been widely used for drug discovery as they can be scaled up.

Researchers can gain rich biological insights and replicate key aspects of human pathophysiology by combining CRISPR screens with sophisticated models like human cell lines, tissue explants, animal models, and organoids. CRISPR's high sensitivity and single-base specificity make it a powerful tool for identifying and validating potential drug targets.

With ongoing advancements and further research, CRISPR is poised to continue shaping the future of medicine and biology, offering new possibilities for precise and personalized treatments.