The Cutting Edge: Gene Editing
In our article series we unpacked the science behind gene therapy and how this powerful technology will likely change business models. While gene therapy is here now, with several drugs already approved by the Food and Drug Administration (FDA) and hundreds more applications in queue, gene editing is at the cutting edge of technology and still in the early stages of clinical testing. Here we explore how this permanent genetic solution is applied and the industries that could emerge with the advancement of this technology.
In our first article, we considered gene therapy, which enables the delivery of entire genes to a cell, often through viruses that can be used as couriers to deliver corrected genes to the cells that have an incorrect copy of the gene. By contrast, gene editing is the process of changing a patient’s DNA by introducing deletions, insertions, knockouts and point mutations to fix the root cause of a disease, using enzymes as “molecular scissors” to precisely cut and alter DNA permanently. Thus, while gene therapy enables the addition of a new extrachromosomal gene to a cell, gene editing enables direct alteration of a patient’s DNA.
Consider a Cystic Fibrosis patient with a mutation referred to as delF508 in their cystic fibrosis transmembrane conductance regulator, or CFTR, gene. With gene therapy, a virus can introduce a corrected CFTR gene. In comparison, gene editing aims to permanently correct that deletion in the patient’s DNA. While the durability of gene therapy is still under investigation, gene editing will always be a permanent alteration to the cell and all of its progeny. Both gene therapy and gene editing carry a theoretical oncogenic risk—either inadvertent integration of the transgene or off-target gene editing; however, we have not yet seen any cases of this.
How it Works
For the sake of simplicity, we focus here on the most common gene editing approach, which uses the CRISPR/Cas9 enzymes. Combining Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), Cas (CRISPR-Associated protein 9) and a guide RNA, we can find and cut targeted DNA sequences. After which, the cell’s DNA repair mechanism can respond in a few different ways. In the absence of a corrected DNA template, the two cut ends are trimmed and then rejoined, either through Non-Homologous End Joining, (NHEJ) or Homology Directed Repair (HDR). This process introduces changes that disrupt the reading frame of the gene and result in decreased expression of certain genes or regulatory sequences.
CRISPR/Cas can be delivered ex vivo (outside the body), for example, by taking stem cells from a patient, editing, proliferating and finally giving them back to the same patient. Alternatively, gene editing can be done in vivo (within the body). Thus far, most clinical trials have focused on editing cells ex vivo, so that the edits can be monitored for correctness. For example, CRISPR technology has been utilized to introduce a deletion in the regulatory domain of the BCL11a gene, which results in expression of fetal hemoglobin, a protein that is normally repressed in adults. This type of approach has shown remarkable results in the treatment of Sickle Cell Disease and Beta Thalassemia, dramatically reducing or eliminating patient reliance on blood transfusions. In particular, one patient went from requiring an average of 16 transfusions per year to being transfusion free nine months after therapy. Combined, Sickle Cell Disease and Beta Thalassemia impacts approximately 100,000 patients in the US according to the CDC.
The Future is Now
In 2020, we will see the first patient dosed in vivo using CRISPR technology. There are two main delivery systems for CRISPR in vivo—either packaged within a virus or encapsulated within a lipid nanoparticle (LNP). While LNP delivery will restrict activity largely to the liver (where the LNPs will accumulate), it also enables the potential for repeat dosing, so the CRISPR effect could be titrated to the desired impact. Conversely, viral-based delivery can target particular cell types, but can only be given once as the patient is effectively immunized against the virus after the first exposure.
Looking forward, we are still in very early days of determining the real power of CRISPR technology. Not only can CRISPR be the therapy, but it can also be a platform to identify new drug targets that will drive robust future growth in fields such as oncology. We also expect we will continue to build off of CRISPR capabilities with added modalities so that we can edit individual bases in DNA. This is a rapidly developing field of biotechnology that will drive future growth for decades to come. With these remarkable new technologies, we can dramatically improve patients’ lives, offering them better outcomes and freedom from chronic therapies. We can also decrease physician burden. Despite the initial sticker shock at the cost of some of these drugs, we believe that durability of effect will ultimately be cost-saving to the healthcare system over time.
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