CRISPR
Joey Sweeney, PharmD, BCPS
Cancer. The diagnosis is terrifying and is often viewed as a death sentence. Most people valiantly fight against this disease, and some prevail. Chemotherapy, radiation, and surgery are often used, but while they inflict damage on the cancer, they often damage healthy tissue as well. Unfortunately, many patients are unable to tolerate these blunt effects and focus instead on maximizing the time they have left being as comfortable as reasonably possible.
True advancements in cancer treatment and prevention have not come to fruition. Vaccines hold promise to prevent certain cancers, but these are not silver bullets, and their usefulness is limited to certain specific cancers. A true paradigm shift has not occurred within the past 30 years—until today.
CRISPR as a treatment option
CRISPR technology has recently been shown to be a promising safe treatment option. Once additional safety studies are performed, this powerful tool may be what the world has been waiting for to battle cancer.
In healthy cells, when growth reaches a certain threshold, the machinery used to create more of the same cells is turned off, preventing a group of cells from growing and dividing uncontrollably.
In general, cancer occurs when this machinery stops working correctly and uncontrolled growth, mediated by a mutated gene, occurs. In the past, there was no way to find cells that contained this mutation and shut them down.
Today, CRISPR technology promises to do exactly that: Find these mutated genes and destroy them, effectively destroying all cells that have cancerous activity.
CRISPR has the potential to revolutionize how we treat virtually every disease. We currently focus on managing symptoms of disease, and, in general, work “downstream” of the genetic culprit of disease. Literally curing cancer (not just putting it into remission)—along with curing hundreds to thousands of other diseases—is possible.
CRISPR safety
Before the floodgates of cures open, we first need to understand the safety implications of editing our genomes using CRISPR.
Despite being very specific—that is, targeting a sequence of 20 nucleotides—it is possible that CRISPR could result in collateral damage to nondiseased portions of DNA.
If we use a 20-nucleotide sequence that identifies a cancer-causing sequence of DNA, it is possible that this sequence also exists elsewhere within the 6-billion-nucleotide sequence that comprises the rest of the genome.
If this specific sequence also codes for a necessary gene—perhaps the gene that tells your bone marrow how to make red blood cells (RBCs)— using CRISPR would not just kill all cancer cells, it would also destroy the patient’s ability to make RBCs.
This is just an example of what could go wrong, not necessarily what would go wrong.
Phase I trial
Recently, studies on the safety of CRISPR technology in human patients have begun in the United States. Eighteen patients are slated to receive therapy with this technology; three have received it so far. The results of the treatment of these three patients were presented at the American Society of Hematology annual meeting in December 2019.1
In this Phase I trial, Edward A. Stadtmauer, MD, and colleagues from the University of Pennsylvania’s Abramson Cancer Center enrolled patients who had exhausted all other relevant treatment modalities for their cancer.
The CRISPR technology is deployed by removing autologous T-cells (a kind of white blood cell) from the patient. Then, the CRISPR Cas9 protein was transfected into these cells.
Now armed with these new weapons, the T-cells were infused back into the patient, where they went on to multiply into a persistent and regenerative army that will continually rove through each patient, looking for specific cancerous genes and shutting them down when they are found.
The researchers observed the cells expand and bind to their tumor targets with no serious adverse effects. Two patients experienced mild adverse effects that were manageable, and no neurotoxicities or cytokine release syndrome was observed.
The third patient has not been enrolled in the study long enough to make a safety determination.
In addition, the authors indicated that the technique shows promising efficacy, but given that this is a Phase I trial, definitive efficacy evaluation is not in scope.
Time will tell if these and other patients experience the intended anticancer effects of the therapy. If they do, their lives will be changed in a way no other human with cancer has experienced.
They will have a literal army of soldiers working day and night within their blood to seek and destroy cancer-causing genes within their bodies, with little to no adverse effects or rejection risks.
They will be cured.
Reference
https://ash.confex.com/ash/2019/webprogram/Paper122374.html
What is CRISPR?
CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is a powerful tool that allows researchers to easily alter DNA sequences and modify gene function.
Nucleotides—DNA’s four building blocks—are used to code sequences that are converted to a messenger molecule called RNA. For RNA to be transcribed from DNA, various coding mechanisms guide the transcriptase proteins where to go, where to start, and where to stop. This RNA travels to ribosomal subunits within the cell where it is used to create proteins.
Part of the coding strategy used by DNA employs various repeats and spacers, nucleotide information that is useful to the cellular machinery used to transcribe RNA but does not contain information contained in the transcription.
CRISPR technology relies on these repeats and stops to identify where a specific gene exists. Specifically, CRISPR uses a protein called Cas9 (which stands for CRISPR-associated protein 9) that compares the DNA in a cell with the DNA sequence it is seeking. It attaches to DNA and roves along the strand, comparing what it “sees” with the sequence it has been assigned to “find.”
Once it finds this sequence, this Cas9 protein generally cleaves the DNA at this sequence, rendering it useless.
Other forms of CRISPR technology allow for other mechanisms of action at this target site, but the result is generally the same—the gene is inactivated. The sequence of nucleotides the Cas9 protein searches is 20 nucleotides long, which allows for enough specificity to target individual genes on a DNA molecule.