Clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated protein (Cas) systems are programmable genome editing tools that can mediate site-specific DNA modifications. Although gene-editing technologies, including CRISPR, enable highly specific treatments tailored to individuals, their clinical success depends on overcoming issues like efficiency, gene correction specificity, and precise cell targeting. Here, we'll discuss the potential gene-editing technologies like CRISPR have for personalised therapies, as well as the challenges and regulatory landscape that affect its clinical uptake.
Genetics plays a pivotal role in the complex web of human diseases. While our understanding of how genes influence disease progression, development, and susceptibility continues to evolve, we've made significant strides in pinpointing specific genes linked to various conditions. This knowledge has led to the concept of repairing or eliminating harmful genetic mutations. By addressing the root cause, which in many cases is a specific mutation triggering a condition, we hold the potential to substantially reduce the risk of its development. This is where genome editing technology steps in, offering the means to make these precision alterations.
Genome editing modifies genomic DNA to change the genetic information artificially, through both gain-of-function (e.g., gene knockin, gene activation) and loss-of-function (e.g., gene knockout) mutations. Gene therapy uses both genetic testing and genome editing to offer personalised treatments. The process begins with a thorough examination of a patient's genetic makeup to identify specific mutations that could benefit from intervention. Then, gene editing technology is used to finely tune gene expression, ultimately shaping the desired genotype.
CRISPR and Cas systems are some of the latest gene editing tools. In its early applications, this technology was harnessed to allow prokaryotes, such as archaea and bacteria, to identify, process, and retain fragments of viral DNA. This capability played a crucial role in developing immune response mechanisms in these organisms. However, it has now evolved to be able to edit genes in mammals; a DNA strand can be specifically cut in vitro for therapeutic purposes. While there are several different types of CRISPR technologies, CRISPR-Cas9 is one of the most commonly used genome editing techniques due to its ease of use, versatility, and precision.
CRISPR-Cas9 is currently being used by geneticists and medical researchers to edit parts of the genome by removing, adding or altering sections of the DNA sequence.
The CRISPR-Cas9 system relies on two vital components: Cas9, acting like "molecular scissors" to precisely cut DNA at a specified location, and guide RNA (gRNA), which includes a short, pre-designed RNA sequence within a longer scaffold. The guide RNA is carefully crafted to bind to a specific DNA sequence by matching its RNA bases to the target DNA sequence. This precise binding directs Cas9 to the intended genomic location to drive accuracy.
Once Cas9 is guided to the precise location by the guide RNA, it makes a cut across both strands of the DNA. At this point, the cell recognises that the DNA is damaged and begins to repair it. Importantly, scientists can harness this DNA repair process to make specific changes to one or more genes in the genome of a cell that they would like to modify.
CRISPR has already shown promise in targeting and treating a wide range of genetic conditions – for example, certain types of cancer. Cancer is influenced by both genetic and epigenetic factors and current treatments often fall short because of its complex nature. However, in combination with next-generation sequencing (NGS), CRISPR shows promise in expediting the identification, validation, and targeting of key elements involved in the disease. This approach can potentially lead to more effective and precise cancer therapies, addressing the heterogeneity of cancer by tailoring treatments to each patient's genetics.
In addition, CRISPR is also being used to identify new drug targets and biomarkers and help us to further understand drug resistance mechanisms. There are many potential benefits of using CRISPR-based treatments, including:
CRISPR aids the development of highly-targeted therapies that could transform the way we treat and manage various genetic conditions, ultimately improving patient outcomes and quality of life. However, there are some challenges and ethical issues to consider.
Off-target effects and precision: One of the foremost concerns is off-target effects, where CRISPR may inadvertently edit genes other than the intended target. These off-target alterations can lead to unintended consequences and pose risks to patient safety. Achieving a higher degree of precision is crucial to minimise these off-target effects and ensure that CRISPR operates as accurately as possible.
Delivery mechanisms: Efficiently delivering the CRISPR components to the target cells is another significant hurdle. The in vivo delivery of the CRISPR system remains a challenge, as it requires the safe and precise transport of these gene-editing tools to the desired location within the body. The development of better delivery methods is imperative to make CRISPR treatments more effective and accessible in clinical settings.
Unintended mutations: When attempting to correct genetic mutations, there is the risk of introducing unintended mutations during the editing process. These unintended changes could lead to unforeseen health issues, emphasising the need for meticulous oversight and rigorous safety protocols in the application of CRISPR technology.
Long-term effects and ethical considerations: The long-term effects of gene editing on human health and the potential ethical implications are subjects of intense debate. Modifying the human genome raises profound questions about the consequences of such alterations for future generations and the broader ethical implications of playing with the fundamental building blocks of life. Striking a balance between scientific progress and ethical considerations is an ongoing challenge that requires careful thought and regulation.
While ethical considerations and a lack of current regulatory guidance on gene-editing technologies have slowed clinical uptake overall, there have been significant developments lately. For instance, the FDA, EMA, and MHRA have each received regulatory filings this year for exagamglogene autotemcel ("exa-cel"), a novel treatment for sickle cell disease and transfusion-dependent beta-thalassemia using CRISPR technology, with the FDA scheduling their decision on the sickle cell indication for December 2023.
Bringing gene-editing tools to the market is a process that takes time, and as these potential treatments near approval, concerns about pricing and reimbursement come into focus. It is vital to establish fair pricing structures to ensure that people, especially those with rare diseases, can access these treatments, even when the patient pool is small. In Europe, the approval process is further complicated because pricing and payment agreements must be negotiated separately with individual countries and regions, potentially hindering patient access to necessary therapies. Additionally, ongoing discussions revolve around defining and categorising genome-editing products, particularly when they are administered using different methods.
CRISPR-associated systems and other gene-editing tools hold great promise in tackling hereditary diseases, viral infections, and cancer, and they are expected to play a pivotal role in the future of healthcare. However, this path to progress must be navigated with responsibility, transparency, and ethical consideration at every step. Equally important is acknowledging the importance of confronting challenges like editing efficiency, delivery techniques, and minimising off-target effects. And, at the same time, it is crucial to establish a harmonised regulatory framework, both on an international and domestic level, to ensure that individuals who stand to benefit from these treatments can readily access them.