Applications of CRISPR
The main driving factors behind the speed and extensive uptake of the technique by industry are its elegant simplicity, its relatively low cost and ease of developing protocols for its use. A further factor is the flexibility of the system and the wealth of natural CRISPR systems present in bacteria and archaea, which provide models for study and further refinement/improvement of the technology. They also provide a source for the discovery of new forms of Cas proteins or CRISPR system subtypes with different properties and technical applications
CRISPR in gene editing
CRISPR is not the only or even the first technique developed for gene manipulation/editing – older technologies employing Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs) have been known, and have been the subject of much interest and investment, for years. However, both of those techniques are commonly regarded as difficult to use, and require the creation of an entire bespoke protein to interact with any given nucleic acid sequence.
CRISPR and personalised medicine
The advent of personalised medicine has been made possible by inexpensive genome sequencing technology and ever-more sophisticated biochemical tools. These have fuelled efforts to create targeted therapies specifically tailored to cater for the genetic identity of a particular patient, or to target specific genetic variants of a condition or disease.
The arrival of CRISPR and its facilitation of simpler, more precise methods to insert or delete genes, or differentially regulate their expression will further expedite the development of personalised medicine. Each of the original key players involved in CRISPR have already entered into further collaborations with major pharma companies, venture capitalists and biotechs in respect of a number of promising fields of research such as chimeric antigen receptor T-cell therapy, designed to target cancer cell antigens specific to the patient’s cancer and haematopoietic stem cells, resulting in huge investment and industry interest.
CRISPR clinical trials
On 28 October 2016, clinical trials involving CRISPR based gene editing commenced in China, using CRISPR modified PD-11 disabled T-cells to treat patients with aggressive lung cancer.
Details of the University of Pennsylvania’s ambitious CRISPR-related clinical trial (the first to receive approval in the U.S.) emerged in 2016, but as of January 2018 it is unclear whether any patients have yet been treated. The UPenn trial aims to use CRISPR to perform three different genetic modifications on T-cells from patients with myeloma, sarcoma or melanoma, using CRISPR not only to disrupt PD-1 receptor expression, but also to knock out portions of the T-cell’s primary receptor. The reason for the latter is to maximise the effect of a further (non-CRISPR based) modification the researchers will make to the T-cells – introducing an engineered NS ESO-1 receptor to the T-cell. By knocking down/out the primary receptor, preventing PD-1 mediated T-cell deactivation and introducing this engineered new receptor, it is hoped that the T-cells will selectively hone in on NS-ESO-1 antigen displaying cancer cells.
CRISPR beyond the biomedical sphere
Although much of the media coverage to date has tended to focus on the potential medical applications for CRISPR technology, equally there are a wealth of potential applications in the agricultural, food and bio-industry sectors. Indeed, CRISPR is likely to be relevant in any industry in which genetic technology may be used to alter, improve or investigate a state of affairs. Barrangou and Doudna’s 2016 Nature Biotechnology article (Nature Biotech. 34(9) 933) describes these potential applications in detail.
Given the amount of research and development required to demonstrate the efficacy and safety of human therapeutic products and to generate the clinical data to support a submission to the regulatory bodies for a marketing approval, the first CRISPR-based human therapeutics are still a number of years off yet. CRISPR Therapeutics submitted the first Clinical Trial Application for a CRISPR-based therapy in December 2017, (its lead pipeline prospect, CTX001, for the treatment of beta-thalassemia).
Other than CRISPR-related basic research tools (which is already a large and growing field), the industry in which CRISPR products are most likely to become available is agriculture. Because CRISPR-based editing (not to mention ZFN and TALEN editing) does not involve the incorporation of foreign transgenes into the edited organism, such edited products are not caught by many of the regulations designed to capture the transgenically modified products that have traditionally been defined by the term “GMO”. With the advent of climate change and a growing acknowledgement of the need for global food security, CRISPR-edited crops from the likes of DowDuPont and Bayer Crop Sciences may become available much sooner than some realise.