You’ve probably heard something about CRISPR (even if you don’t know that it stands for Clustered Regular Interspaced Short Palindromic Repeats!). It’s is a powerful gene-editing technology that's garnered a lot of attention recently as it's quicker to use, cheaper, and potentially more accurate than other gene editing techniques. And crucially, it’s now heading toward the clinic, where it could be used to correct faulty genes.
What exactly is CRISPR?
CRISPR was first identified in bacteria as naturally occurring defense mechanism against invading pathogens, where it snips out parts of the invader’s DNA so that it is recognized if the attack occurs again. It was then appreciated that CRISPR had the potential to be used as gene editing technique in eukaryotic cells – key scientific papers were published by separate groups of researchers at the University of California and the Broad Institute in 2012–2013.
When CRISPR is used as a gene editing tool in eukaryotic cells, scientists design a specific RNA sequence, known as guide RNA, which brings an enzyme called Cas-9 to a specified part of the cell’s genome. Cas-9 then cuts the double stranded DNA, and then the cell's own DNA repair machinery is used to add, delete or make changes to the DNA by replacing an existing segment with a customized DNA sequence.
The potential of CRISPR
With CRISPR, the Cas9 enzyme can be directed to any DNA sequence, just by providing it with a guide RNA molecule, meaning that it’s much easier to synthesize than other gene editing technologies – such as TALENs and zinc finger nucleases. And since the CRISPR-Cas9 system itself is capable of cutting DNA strands, CRISPRs do not need to be paired with separate cleaving enzymes as other tools do.
CRISPR has great potential in the lab, where it can be used to quickly create cell and animal models of human diseases, so accelerating research. The idea that CRISPR could accelerate the gene-therapy field has created a big buzz and it offers hope for patients with disorders that were once considered incurable. Laboratory studies are underway looking at the potential of CRISPR to cure beta-thalassemia, sickle cell disease, hemophilia, Duchenne muscular dystrophy, cystic fibrosis and Huntington's disease amongst others.
Into the clinic
However, clinical studies are still very much in their infancy. Even the most advanced study, which reportedly treated over 80 patients with lung cancer in China, does not have results available.
Of the CRISPR trials listed on ClinicalTrials.gov, all are for cancer, and are either still recruiting, or not yet underway (Table 1). Many of these studies involve collecting patients’ own cells (such as T cells and stem cells), then using CRISPR to knock out a specific cancer-linked gene in the laboratory, then expanding the population of cells and infusing them back into the patient.
Challenges and future opportunities
Although the CRISPR field seems to be moving ahead at pace, there are concerns about potential off-target effects, which could occur if there is more than one nucleotide sequence in the genome that is recognized by the guide RNA. This could for example silence a tumor-suppressor gene or activate a cancer-causing one.
But efforts are underway to get a better understanding of and mitigate these potential issues. Research into new versions of the Cas enzymes, such as cpf1 hope to increase the specificity of CRISPR, and alternatives to the usual viral delivery methods – as gold nanoparticles – hope to reduce concerns about immune responses.
More researchers and companies are harnessing the power of CRISPR for accelerating research. But perhaps the biggest opportunity will be realized when the clinical trials begin to read out.
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