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CRISPR: An up close and personal take on precision medicine

Published on 06/04/17 at 11:09am

Traditional approaches to patient therapies are increasingly showing their age inefficacy, but a powerful new gene editing technology is making waves across a number of scientific areas. Matt Fellows explores the impact of this revolutionary new tool and what it could mean for the future of precision treatment.

Precision medicine has been a powerful trend emerging in treatment research, development and delivery over the past four years. It refers to the use of cutting-edge diagnostic and informatics tools, to better identify the individual characteristics of the patient, so that their unique profile may inform prevention and treatment of disease.

By stratifying patient traits into subpopulations based on their response to treatment, level of disease susceptibility and other criteria, a detailed picture of differing patient populations can be generated. This allows medical professionals to quickly and efficiently identify who is at the greatest risk to specific illnesses and who will benefit from a particular therapy. This means that therapies are only administered to those who are known to benefit from them, while all other unresponsive patients avoid sometimes severe adverse reactions.

The central thought behind the movement is that if patients whose genetic signatures make them more responsive to specific therapies, or more vulnerable to particular diseases, can be identified pre-emptively and stratified, more comprehensive disease models can be created; from this, more novel, targeted treatments can be designed and developed.

While it has been gathering speed in the scientific community for some time, precision medicine’s following grew to even greater proportions with the launch of former US President Barack Obama’s $215 million Precision Medicine Initiative in January 2015. The project was designed to expand the application of precision medicine methodology, particularly in the cancer sphere. Obama clarified the role of the initiative in his State of the Union address: “Doctors have always recognised that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type; what if matching a cancer cure to our genetic code was just as easy, just as standard?”

As part of the initiative’s operation, the National Institute of Health aims to conduct a study of at least one million US patients in an effort to develop greater understanding of precision medicine function and application, collecting genetic data and biological samples into a national database in order to build better models of disease risk.

Wider adoption of the methodology has become increasingly supported and called-for in the scientific community as the unsuitable nature of the standard, blanket approach to treatment becomes more and more apparent. Nicholas J Schork, in his commentary Personalized medicine: Time for one-person trials for Nature, refers to the phenomena of “imprecision medicine”. He explains this to be a trend emblematic of the traditional and antiquated methodology exercised in modern medical treatment that sees millions of patients taking medication daily which they will not respond to; it has been estimated that only 30%-70% of patients respond positively to drug-based treatment.

Schork notes that the true figure is likely much lower. According to findings detailed in the report Pharmacogenomics in cardiovascular diseases, the one-size-fits-all approach to treatment in the past has led to a climate where as few as one in 25 patients in the US will benefit from some of the best-selling and most prescribed drugs in the market. Of the top ten US drugs, response rates vary wildly from 25%, for drugs such as Humira (adalimumab), Enbrel (etanercept) and Remicade (infliximab), to a staggeringly minute 4% for Nexium (esomeprazole). This paints a sobering picture of the ineffectuality of the “imprecision” approach for a considerable section of patients who find themselves left behind on decisive treatment.

This drastic data places the real problem of drug ineffectuality into perspective for patients in today’s medical landscape. Obsolete, scattergun techniques have led to a climate where even the most subscribed treatments do not actually benefit the majority of their users, and this is one of the primary factors driving a motion towards a more targeted approach to treatment. One of the key tools with applications in this field is CRISPR.

Rewriting the book

Clustered regularly insterspaced short palindromic repeats, or CRISPR, are sections of prokaryotic DNA which contain short, repetitive base sequences, and scientists have married this discovery with a protein called cas9 (CRISPR associated system 9) which acts as a ‘molecular cleaver’, enabling researchers to actually cut DNA. The implications of this are that a segment of DNA can be cut and removed using cas9, meaning segments of a human genome can be taken from the human body, edited, and reintroduced in order to correct faults which could lead to the manifestation of serious disease or other harmful effects. Particularly, CRISPR promises big things for the treatment of diseases which have been identified as being caused by established genetic faults, such as sickle-cell anaemia and cystic fibrosis.

Jennifer Doudna, Professor of Chemistry and Molecular and Cell Biology at the Department of Chemistry and Chemical Engineering of the University of California, commonly referred to as the foremother of CRISPR, has been instrumental, not only in the technology’s development but also in communicating its benefits:

“This is a tool that is so precise that it allows changes to be made to the DNA that are much more accurate than could have been achieved by previous technologies,” she details. “So it means that once one understands the sequence of DNA in a cell, it’s possible to rewrite that sequence to recode the genome in a sense, and to do so in a way that will either cure fixed mutations that cause genetic disease, or allows scientists to understand the functions of genes that we currently don’t know the function of.”

The tool is currently in use by teams around the globe to explore and understand the scope of how genetic editing can aid in the treatment of patient disease. Dr Krishanu Saha, Assistant Professor of Biomedical Engineering at the University of Wisconsin-Madison, has been working with his team to observe gene editing in action using CRISPR in order to develop improved genetic engineering techniques. Pharmafocus spoke with him to discuss how the revolutionary technology works and what it means for the field of precision treatment:

“CRISPR is essentially a two-component system: one component is a protein and one component is a ribonucleic acid (RNA),” he explained. “It’s modular such that the RNA sequence essentially directs the protein to cut at a particular sequence in the genome. If you wanted to have a cut in a specific spot in a genome, for all of the other technologies you’d have to engineer the protein each time for each locus. Here, all we have to do is swap out the modular RNA portion, and that allows us to rapidly understand the function of one protein. Then any researcher can type in a sequence of RNA and get it synthesised, essentially overnight, and then generate a cut at that specific spot in the genome the next day.”

A personal approach

While gene editing had existed prior to the development of CRISPR, the speed and accuracy the technology provides is leagues ahead of of what was previously possible, as Saha notes: “That kind of quick turnaround is just phenomenal for the field.”

“When I started my lab here at Wisconsin in 2012, it was a pretty laborious process,” he adds. “We had to engineer some nucleases and it would take months for us to find something that would cut with each specific gene variant, and then we would have to screen whether those cuts could create proper corrections. Now, with the CRISPR tools we have been developing, we can do that in a period of weeks, if not days. So that timescale has really shrunk, and I think that makes it feasible for a lot of conditions where you’d want to take out cells, do an ex vivo gene manipulation and then put that cell back in the body; there are some conditions where that could be a pretty important workflow.

“Turnaround is one thing, the other thing is multiplexing,” he continues, “meaning that you can not only go after one spot on a genome, but go after thousands of spots on a genome, or potentially the whole genome and disrupt it in tens of thousands of spots. Some of the more elegant work in the field has been to identify drug targets by cutting systematically across thousands of potential drug targets and then inferring from the results of their culture assay: what is the exact amino acid that the drug is targeting? Because they’ve systematically disrupted every amino acid in the candidate drug target. That level of systematic gene modification was just not feasible four years ago.”

CRISPR has supercharged what scientists are able to achieve in the gene editing sphere, and this technology has a range of applications for use in precision therapies, enabling treatments which incorporate a patient’s genetic profile or the development of more robust disease models from this genetic data. Saha offers some examples of how CRISPR technology could be utilised in a personalised context:

“Generating a tissue-like mimetic that resemble what’s going awry in your body, that could be done in a matter of weeks or months,” he explains. “And then being able to systematically perturb drug targets at a genetic level and then see whether those change the course of disease in the lab; that is a preclinical test that’s personalised, and you could do that systematically for every candidate drug that a physician is thinking about.

“Another area is gene correction,” he continues. “You can generate a CRISPR therapeutic that is specific to that person’s genetic variant. You can imagine the various places in a spectrum of muscular dystrophy patients: each have a different gene variant but basically use the same exact CRISPR strategy, except that the RNA sequence is personalised to that person’s gene variant. So that’s a class of therapeutics that I think will be inherently either stratified to a group of patients that have the same gene variant or even personalised to the exact mutation that a person has.”

A slippery slope

Despite the groundbreaking potential of this technology for the precise treatment and prevention of serious disease, CRISPR has drawn ire from ethical groups due to the perceived dangers of the ‘slippery slope’ it could lead to. By unlocking the ability to edit the human genome to remove or correct potentially harmful or ineffective genes and therefore eliminate the threat of various ailments, concern has been raised that, in the absence of clearly-defined ethical boundaries, use of the technology could easily slip into ‘designer baby’ territory. The technology presenting particularly useful applications in ‘germ-line’ modifications – that is, in human embryos, eggs and sperm – editing the genes of unborn babies to avoid them being born with preventable and sometimes otherwise unavoidable diseases. However, opposition groups have argued that this could lead to parents choosing to modify their child on cosmetic or trivial levels – a step, they argue, that is dangerously close to eugenics.

This debate took a significant leap in February this year when the use of CRISPR was endorsed in germ-line applications by a panel of experts from the US National Academy of Sciences and the National Academy of Medicine, but only in situations where it is “really the last reasonable option for preventing a serious disease or condition,” such as in children whose parents both suffer from serious inheritable diseases. A report from the two academies stated: “Heritable germ-line genome editing trials must be approached with caution, but caution does not mean that they must be prohibited.” The debate is certain to carry on in earnest, but the recognition of the technology’s vast potential is huge step forward on the road to eliminating serious diseases.

The best is yet to come?

The technology is still very much in the embryonic phase, and although the applications its presents are vast, much of its true potential is still to be realised. While CRISPR is making huge strides in the science world today, the tool opens the door for many theoretical treatment paths in the future which could allow for targeted therapies applied on a patient-by-patient basis and manipulated on a cellular level.

“Farther off, you can think about particular engineered cells having specific behaviours for each person’s condition” Saha says, “so in the cancer space you may want to have the CAR T-cells migrate to a particular spot, kill only for a particular duration and then commit suicide and be eliminated from the body – that might not be the case for the patient next door to him or her. These types of behaviours could be personalised and controlled by the physicians or through some sort of triggers that are engineered into the cells. I think that’s where the field is going: having much more control over these cells that we are putting into patients and potentially being able to control them in ways that are personalised for that person’s condition.”

CRISPR caused a buzz amongst researchers when it first emerged into the science world, and that buzz, partially fuelled by the controversy which was always bound to come with such a revolutionary technology, shows no sign of fizzling out. Even beyond its implications on precision medicine, CRISPR can be applied to range of areas, some even outside of healthcare, as Professor Doudna notes:

“It’s been appreciated that one could employ this technology for things that are of very practical and important value in human health, in agriculture, for protecting the environment. So I think this is something that gives this technology an impact that we could only imagine when we got started.”

The possibilities of the tool are tremendously exciting, and institutions are committing resources to realising its power in the precision medicine space and beyond; according to Saha, the future is looking bright. He shared with us some of his predictions on where the field could move next:

“I’m very excited about some of the clinical trials that are going to be coming out, especially in the oncology space,” he tells us. “I think more and more functionality will be put into somatic cells; I see the CAR T space as just the tip of the iceberg in terms of genetic circuits that could be put into the blood. I also think the gene editing companies that are working with CRISPR are doing exciting work, going after inherited diseases; those trials typically involve kids, and sometimes you can get really amazing and quick outcomes from those that may be harder to get later.”

But, of course, there’s still far to go to ensure efficacy and safety of treatments in patients: “I think there’s still some really, really important research to be done about quality and safety and effectiveness of all the advanced therapies, but then there’s also a lot of commercial interest, understandably, trying to push these therapies into patients that are demanding them. That type of balance is something that I think has been hard to strike here in the US and probably across the world; I’m hoping that all these companies and researchers are responsible and understand this balance.”

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