Could CRISPR really cure these diseases? 

CRISPR technology offers the promise to cure human genetic diseases with gene editing. This promise became a reality when the world’s first CRISPR therapy was approved by regulators to treat patients with sickle cell disease and beta-thalassemia three years ago.    

American biopharma Vertex Pharmaceuticals’ CASGEVY works by turning on the BCL11A gene, which codes for fetal hemoglobin. While this form of hemoglobin is produced before a baby is born, the body begins to deactivate the gene after birth. As both sickle cell disease and beta-thalassemia are blood disorders that affect hemoglobin, by switching on the gene responsible for fetal hemoglobin production, CASGEVY presents a curative, one-time treatment for patients.  

As CASGEVY’s clearance is a significant milestone, the technology has come a long way. CRISPR/Cas9 was first used as a gene-editing tool in 2012. Over the years, the molecular scissors technology exploded in popularity thanks to its potential for making gene editing faster, cheaper, and easier than ever before. 

How does CRISPR technology work? 

CRISPR is short for clustered regularly interspaced short palindromic repeats. The term makes reference to a series of repetitive patterns found in the DNA of bacteria that form the basis of a primitive immune system, defending them from viral invaders by cutting their DNA. 

Using this natural process as a basis, scientists developed a gene-editing tool called CRISPR/Cas that can cut a specific DNA sequence by simply providing it with an RNA template of the target sequence. This allows scientists to add, delete, or replace elements within the target DNA sequence. Slicing a specific part of a gene’s DNA sequence with the help of the Cas9 enzyme, aids in DNA repair. 

This system represented a big leap from previous gene-editing technologies, which required designing and making a custom DNA-cutting enzyme for each target sequence rather than simply providing an RNA guide, which is much simpler to synthesize. 

CRISPR gene editing has already changed the way scientists do research, allowing a wide range of applications across multiple fields. Here are some of the diseases that scientists aim to tackle using CRISPR/Cas technology, testing its possibilities and limits as a medical tool. 

CRISPR for cancer 

Cancer is a complex, multifactorial disease, and a cure remains elusive. There are hundreds of different types of cancer, each with a unique mutation signature. CRISPR technology is a game-changer for cancer research and treatment as it can be used for many things, including screening for cancer drivers, identifying genes and proteins that can be targeted by cancer drugs, cancer diagnostics, and as a treatment. 

China spearheaded the first in-human clinical trials using CRISPR/Cas9 as a cancer treatment. The study tested the use of CRISPR to modify immune T cells extracted from a patient with late-stage lung cancer. The gene-editing technology was used to remove the gene that encodes for a protein called PD-1 that some tumor cells can bind to block the immune response against cancer. This protein found on the surface of immune cells is the target of some cancer drugs termed checkpoint inhibitors. 

CRISPR technology has also been applied to improve the efficacy and safety profiles of cancer immunotherapy, such as CAR-T cell and natural killer cell therapies. In the U.S., CRISPR Therapeutics is one of the leading companies in this space, developing off-the-shelf, gene-edited T cell therapies using CRISPR. It has a candidate targeting the CD19 protein in clinical trials.  

Moreover, to address blood cancers, California-based Caribou Biosciences’ vispacabtagene regedleucel is a CRISPR-edited CAR-T cell therapy in phase 1 studies for B cell non-Hodgkin lymphoma. It is a blood cancer starting in infection-fighting B lymphocytes, which are cells part of the lymphatic system. 

However, CRISPR technology still has limitations, including variable efficiency in the genome-editing process and off-target effects. Biotechs like Massachusetts-based Vor Biopharma and Intellia Therapeutics, that were once advancing CRISPR-edited cancer therapies, have both moved away from the space. Vor quit cancer therapeutics amid funding challenges and the latter, Intellia, halted CRISPR trials after safety scares last year.  

Some experts have recommended that the long-term safety of the approach, especially in treating cancer, remain under review. Others have suggested using more precise gene-editing approaches such as base editing, an offshoot of CRISPR that hit the clinic in the U.S. in 2023. 

CRISPR for AIDS   

There are several ways CRISPR could help in the fight against AIDS. One is using CRISPR to cut the viral DNA that the human immunodeficiency virus (HIV) inserts within the DNA of immune cells. This approach could be used to attack the virus in its hidden, inactive form, which is what makes it impossible for most therapies to completely get rid of the virus.  

The first ever patient with HIV was dosed with a CRISPR-based gene-editing therapy in a phase 1/2 trial led by Excision Biotherapeutics and researchers at the Lewis Katz School of Medicine at Temple University in Philadelphia back in 2022.   

The decision to move the therapy to the clinic was bolstered by the success of an analog of the drug EBT-101 – called EBT-001 – in rhesus macaques infected with simian immunodeficiency virus (SIV). In a phase 1/2 study, EBT-101 was found to be safe. Currently, Excision is seeking partners to further develop EBT-101 in the clinic. 

Another approach could make us resistant to HIV infections. A small percentage of the world’s population is born with a natural resistance to HIV, thanks to a mutation in a gene known as CCR5, which encodes for a protein on the surface of immune cells that HIV uses as an entry point to infect the cells. The mutation changes the structure of the protein so that the virus is no longer able to bind to it.  

This approach was used in a highly controversial case in China in 2018, where human embryos were genetically edited to make them resistant to HIV infections. The experiment caused outrage among the scientific community, with some studies pointing out that the ‘CRISPR babies’ might be at a higher risk of dying younger, although this has been disputed since.   

The consensus seems to be that more research is needed before this approach can be used in humans, especially as recent studies have pointed out this practice can have a high risk of unintended genetic edits in embryos.   

CRISPR for hereditary angioedema 

Affecting around one to two in every 100,000 people worldwide, hereditary angioedema is a rare genetic disorder that causes the sudden swelling of the skin, face, limbs, gut, and even the airways, due to fluid leaking from blood vessels, often triggered by minor stress or trauma. With new mutations making up 25% of diagnoses, gene editing therapies could offer something beyond symptom managing-treatments, it could potentially cure it. 

Massachusetts-based Intellia’s approach employs a knockout edit of the mutated KLKB1 gene to curb the excess production of the protein bradykinin, which is linked to inflammation. Currently undergoing phase 3 studies, the therapy, lonvoguran ziclumeran, has exhibited durable reductions in total plasma kallikrein levels, and no severe adverse events have been observed so far. Topline results of the phase 3 trial are expected soon, which will guide its path towards approval. 

CRISPR for cystic fibrosis 

Cystic fibrosis is a genetic disease that causes severe respiratory problems. Cystic fibrosis can be caused by multiple different mutations in the target gene CFTR – more than 700 of which have been identified – making it difficult to develop a drug for each mutation. With CRISPR technology, mutations that cause cystic fibrosis can be individually edited. 

Researchers in the Netherlands used base editing to repair CFTR mutations in vitro in the cells of people with cystic fibrosis without creating damage elsewhere in their genetic code back in 2020. Moreover, aiming to strike again with yet another win is the duo Vertex Pharmaceuticals and CRISPR Therapeutics – the partnership that brought about Casgevy – which have collaborated to develop a CRISPR-based medicine for cystic fibrosis. However, it might be a while until it enters the clinic as it is currently in the research phase.  

Along the same lines, California-based ReCode Therapeutics is advancing a gene correction program using CRISPR-based tools in collaboration with Massachusetts-based Intellia Therapeutics and the Cystic Fibrosis Foundation in Maryland. The therapy is meant to be delivered with a lipid nanoparticle so that it can reach airways where they can edit faulty DNA and restore proper CFTR function.  

ReCode is also advancing a gene correction program to repair the specific mutations in the CFTR gene that cause CF. In collaboration with Intellia Therapeutics and supported by the Cystic Fibrosis Foundation, it is using CRISPR-based tools and its SORT LNP delivery platform to reach airway cells and precisely edit faulty sections of DNA, with the goal of restoring normal CFTR function at the genetic level. It is now in preclinical studies . 

CRISPR for muscular dystrophy 

Duchenne muscular dystrophy is caused by mutations in the DMD gene, which encodes for a protein necessary for the contraction of muscles. Children born with this disease experience progressive muscle degeneration, and existing treatments are limited to a fraction of patients with the condition.   

CRISPR could be used in various approaches to treat muscular dystrophy, namely, exon-skipping, which skips over faulty sections of the DMD gene that disrupt dystrophin production – the protein involved in muscular development. Then there’s exon reframing, which is a method that corrects mutations by adding or deleting DNA. And then a method where cutting DNA fragments is not involved is base editing. Here, by changing a single DNA base, mutations could potentially be reversed. 

Research in mice has shown CRISPR technology could be used to fix the multiple genetic mutations behind the disease. In 2018, a group of researchers in the U.S. used CRISPR to cut at 12 strategic mutation hotspots covering the majority of the estimated 3,000 different mutations that cause this muscular disease. Following this study, Exonics Therapeutics was spun out to further develop this approach, which was then acquired by Vertex Pharmaceuticals for approximately $1 billion to accelerate drug development for the disorder. Currently, Vertex is in the research stage and is on a mission to restore dystrophin protein expression by targeting mutations in the dystrophin gene.  

However, a CRISPR trial run by the Boston non-profit Cure Rare Disease targeting a rare DMD mutation resulted in the death of a patient owing to toxicity back in November 2022. Further research is needed to ensure the safety of the drug to treat the disease. 

CRISPR for Huntington’s disease 

Huntington’s disease is a neurodegenerative condition with a strong genetic component. The disease is caused by an abnormal repetition of a certain DNA sequence within the huntingtin gene. The higher the number of copies, the earlier the disease will manifest itself. 

Treating Huntington’s can be tricky, as any off-target effects of CRISPR in the brain could have very dangerous consequences. To reduce the risk, scientists are looking at ways to tweak the genome-editing tool to make it safer. 

In 2018, researchers at the Children’s Hospital of Philadelphia revealed a version of CRISPR/Cas9 that includes a self-destruct button. A group of Polish researchers opted instead for pairing CRISPR/Cas9 with an enzyme called nickase to make the gene editing more precise. 

More recently, researchers at the University of Illinois Urbana-Champaign used CRISPR/Cas13, instead of Cas9, to target and cut mRNA that codes for the mutant proteins responsible for Huntington’s disease. This technique silences mutant genes while avoiding changes to the cell’s DNA, thereby minimizing permanent off-target mutations because RNA molecules are transient and degrade after a few hours. 

In addition, a 2023 study published in Nature went on to prove that treatment of Huntington’s disease in mice delayed disease progression and that it protected certain neurons from cell death in the mice. And treatments like LETI-101, developed by Massachusetts-headquartered ElevateBio’s gene editing R&D arm, Life Edit, have also demonstrated preclinical success. The CRISPR-edited therapy targets a single nucleotide polymorphism – a kind of genetic variation – in the mutated huntingtin HTT gene. 

Compelling preclinical data found that LETI-101 reduced mutant proteins by more than 80% while preserving normal HTT proteins in mice models, which supports its potential clinical development. 

CRISPR for blood disorders 

With CASGEVY’s go-ahead to treat transfusion-dependent beta-thalassemia and sickle cell disease in patients aged 12 and older, this hints that CRISPR-based medicines could even be a curative therapy to treat other blood disorders like hemophilia.  

Hemophilia is caused by mutations that impair the activity of proteins that are required for blood clotting. Although Intellia severed its partnership with multinational biopharma Regeneron to advance its CRISPR candidate for hemophilia B – a drug that was cleared by the FDA to enter the clinic – the latter will take the drug ahead on its own. 

As hemophilia B is caused by mutations in the F9 gene, which encodes a clotting protein called factor IX (FIX), Regeneron’s drug candidate uses CRISPR/Cas9 gene editing to place a copy of the F9 gene in cells to get the taps running for FIX production.  

The two biopharmas will continue their collaboration in developing their CRISPR candidate to treat hemophilia A, which manifests as excessive bleeding because of a deficit of factor VIII. The therapy is currently in the research phase. 

Meanwhile, blood disorders like sickle cell anemia and beta-thalassemia continue to be researched, and biotechs like Massachusetts-based Editas Medicine have a CRISPR-edited approach in preclinical trials. Its in vivo pipeline is focused on the upregulation and targeted delivery to HSCs, liver, and other tissues, and it has shown promise in a preclinical proof of concept study. 

CRISPR for COVID-19 

While healthcare companies were creating polymerase chain reaction (PCR) tests to screen for COVID-19 in the wake of the pandemic, CRISPR was also being used for speedy screening. A study conducted by researchers in China in 2023, found that the CRISPR-SARS-CoV-2 test had a comparable performance with RT-PCR, but it did have several advantages like short assay time, low cost, and no requirement for expensive equipment, over RT-PCRs. 

To add to that, the gene editing tool could fight COVID-19 and other viral infections.  

For instance, scientists at Stanford University developed a method to program a version of the gene editing technology known as CRISPR/Cas13a to cut and destroy the genetic material of the virus behind COVID-19 to stop it from infecting lung cells. This approach, termed PAC-MAN, helped reduce the amount of virus in solution by more than 90 percent.  

Another research group at the Georgia Institute of Technology used a similar approach to destroy the virus before it enters the cell. The method was tested in live animals, improving the symptoms of hamsters infected with COVID-19. The treatment also worked on mice infected with influenza, and the researchers believe it could be effective against 99 percent of all existing influenza strains.       

However, challenges like ensuring the safe delivery of the CRISPR system remain, which would need rigorous clinical trials to overcome. 

Still, at-home kits born out of CRISPR technology for diagnosing COVID are popular, like the Sherlock and Detectr kits, by Sherlock Biosciences – now acquired by American company OraSure Technologies – and California-based Mammoth Biosciences respectively, can detect viral RNA in under an hour, making them faster than traditional diagnostics tests for COVID. 

CRISPR for high cholesterol 

Cholesterol is a type of waxy blood fat synthesized in the liver, and we need it for the proper function of cells and hormones in the body. However, having too much can clog up the arteries and lead to heart disease. Sometimes, it can be caused by genetic mutations which affects how the body removes cholesterol from the blood resulting in a condition called familial hypercholesterolemia. Around 50% of people with untreated familial hypercholesterolemia will experience a heart attack by the age of 50, according to the Centers for Disease Control and Prevention (CDC). 

CRISPR Therapeutics’ CTX310 is a one-time treatment that uses tiny fat particles to carry the CRISPR editing therapy to the liver. There, it switches off the ANGPTL3 gene, which is linked to cholesterol and triglycerides production.  

A phase 1 study showed that the drug reduced the number of ANGPTL3 proteins circulating in the blood by 73%, triglycerides by 55%, and low-density lipoprotein – a particle that carries cholesterol around, dubbed ‘bad cholesterol’ – by 49%, dramatically lowering the risk of heart disease. 

The future of CRISPR technology 

As European, U.S., and U.K. regulators have given their stamp of approval for the first-ever CRISPR-based drug to treat patients, who is to say we won’t see another CRISPR-drug hitting this milestone soon.  

And apart from the diseases mentioned, CRISPR is also being studied to treat other conditions like vision and hearing loss. In blindness caused by mutations, CRISPR gene editing could eliminate mutated genes in the DNA and replace them with normal versions of the genes. Researchers have also demonstrated how getting rid of the mutations in the Atp2b2 and Tmc1 genes helped partially restore hearing. 

However, one of the biggest challenges to turn CRISPR research into real cures is the many unknowns regarding the potential risks of CRISPR therapy. Some scientists are concerned about possible off-target effects as well as immune reactions to the gene-editing tool. But as research progresses, scientists are proposing and testing a wide range of approaches to tweak and improve CRISPR to increase its efficacy and safety.  

Hopes are high that CRISPR technology will soon provide a way to address complex diseases such as cancer and AIDS, and even target genes associated with mental health disorders.