Tools like CRISPR portend immense promise and unique challenges that stakeholders must consider to ensure effective clinical trial design.
Genome editing has rapidly evolved into a clinical reality reshaping the future of medicine. In just over a decade, technologies like CRISPR-Cas9 have moved from laboratory discovery to regulatory approval (e.g. for sickle cell disease and β-thalassemia), enabling disease-modifying interventions for genetic diseases once considered untreatable.
As clinical researchers explore genome editing, the implications for trial design, short- and long-term patient safety, and therapeutic access are becoming a critical point of discussion among drug developers, clinical researchers, regulators, and other stakeholders in advanced therapies (cell and gene therapy and genome editing). These stakeholders will need to give thoughtful consideration of the nuanced variables that impact genome editing therapies to see their efforts bear fruit.
Adapted for genome editing in 2012, the CRISPR-Cas9 system marked a turning point in biomedical research. The ability to precisely modify DNA by adding, removing, or altering genetic material opened new avenues for treating single gene mutation disorders (e.g. cystic fibrosis, hemophilia, and sickle cell disease), and in recent years, complex diseases. In 2023, the approval of Vertex Pharmaceuticals' and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) for sickle cell disease and β-thalassemia became the first regulatory milestone for an ex vivo CRISPR-based therapy, signaling the shift from experimental to therapeutic use.
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This momentum is not limited to ex vivo treatments. In vivo platforms and novel editors are also being explored clinically in cardiovascular disease, oncology, type I diabetes, liver diseases, muscle diseases, and central nervous system disorders.
For instance, base editing provides next-generation genome editing that uses Cas9 fused to a deaminase enzyme to make single-nucleotide changes to DNA. These systems tend to rely on modified CRISPR nucleases that nick rather than fully break DNA, improving their overall safety profile when compared to traditional genome editing systems. Prime editing works similarly but uses a reverse transcriptase fusion to enable the user to search and replace longer genetic sequences.
Emerging tools, such as epigenetic editors, transposases, and CRISPR fusion systems, are opening possibilities for therapeutic development around more disease indications. Currently, these next-generation technologies are under evaluation, with some expected to progress from preclinical research to human trials over the next several years.
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Despite the promise, advances in genome editing present complex and unique challenges that drug developers must account for when evaluating for safety and efficacy.
Because unintended edits can disrupt healthy genes or activate nearby oncogenes - genes with potential to drive malignant transformations - off-target effects remain a primary concern. This is a key reason that long-term monitoring of patient safety is critical in genome editing. Even when edits occur at the intended site, DNA repair mechanisms can introduce variability leading to unwanted deletions or rearrangements of DNA.
Mosaicism is also a potential concern in the clinic. This occurs when the CRISPR system only successfully edits a subset of target cells. The mixture of edited and non-edited cells can affect efficacy, described as the "therapeutic threshold," which varies depending on the disease, target tissue or cells, and the mechanism of action of the therapy. In some cases, redosing the patient may be possible, although this will depend on the platform (in vivo versus ex vivo) and the method of delivery (lipid nanoparticles or viral vectors). In the case of adeno-associated virus (AAV), for example, immunogenicity constitutes the major short-term safety concern.
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Stakeholders will need to contextualize the potential for long-term efficacy and adverse events, which could occur months or even years after therapy. Here, epidemiological data and additional assessments help establish a potential relationship (or even causality) between therapy and events like malignancies. This makes long-term follow-up critical for genome editing R&D.
These are only some of the variables that drug developers and study teams, including experienced clinical scientists, need to think through as they consider genome editing-specific dosing and delivery pathways and how much of the cells need editing to get a clinical response.
From infrastructure to treatment access to evolving regulatory guidance, there is no shortage of nuances that can impact genome editing clinical trial outcomes. In-depth experience, with demands for specialized scientific, medical, and regulatory expertise, is critical to navigate the inherent complexity, elevated risk, and novelty of genome editing trials.
Short- and long-term patient safety and monitoring is critical in any clinical program for advanced therapies. Regulators require these trials' sponsors to conduct strict assessments and follow-up studies for up to 15 years to detect acute immune or organ toxicities and delayed adverse events. Safety monitoring for multiple years poses unique burdens, especially as patients' lives change (e.g. relocation) and as sponsors try to limit study site burdens while continuing to collect quality data.
Informed consent is an important focus when selecting patients for trials. In genome editing trials, sites and study teams need to thoroughly educate patients about unique risks, benefits, associated procedures, uncertainties, and long-term safety monitoring commitments. For example, in the potentially 15 years of follow-up, patients may consider themselves "cured" and have little interest in additional clinical assessments. This is why it is essential to impart a strong understanding of why these longitudinal evaluations are necessary. These trials currently focus on enrolling individuals with severe treatment-refractory disease. As safety and efficacy data accumulate, there is potential to expand eligibility to earlier stages of disease - but this will require careful focus on risk-benefit profiles and informed consent processes.
Genome editing trials also require specialized infrastructure. Ex vivo therapies, such as those involving edited T cells, require cell processing capabilities, as well as personnel who have experience with procedures, identification, and management of adverse events, and often accreditation in advanced therapies. This limits trial participation globally to a small number of centers, which can slow treatment access.
Genome editing clinical trials present unique challenges and considerations that set them apart from traditional therapeutic development. One of the most critical differences lies in the nature of the intervention itself. Genome editing is often a "one-and-done" treatment, meaning the therapeutic effect is permanent and irreversible. This places immense value on determining accurate dosing through extensive preclinical studies. Unlike conventional therapies where dosing can be adjusted over time, genome editing offers little opportunity for correction. An inaccurate dose could either trigger adverse events or decrease efficacy; often, redosing may not be feasible. Investigators typically address these challenges during well-designed early-phase trials.
Also, because these trials often enroll patients with rare or ultra-rare, difficult-to-treat diseases, genome editing trials typically follow single-arm, open-label designs to determine safety first. Investigators can then incorporate historical data whenever suitable to establish efficacy. However, matching patients with natural history studies can be challenging given inherent heterogeneity in how a disease presents and progresses.
While placebo-controlled trials are rare, the US Food and Drug Administration (FDA) and other regulators are increasingly encouraging randomized controlled trials early in development, especially when external comparators are limited. This complements crossover trial designs in which control arm subjects eventually receive the genome editing therapy to ensure all participants receive potentially the life-saving treatment.
Clinical endpoints in genome editing trials also require a different approach. Traditional clinical outcomes may take time to manifest, so clinical researchers often rely on biomarkers and surrogate endpoints to assess therapeutic impact earlier. These indicators provide early evidence of efficacy and biological activity and are crucial for evaluating novel interventions. This reliance on early signals is another reason regulatory oversight is particularly stringent in the genome editing space. Sponsors must provide comprehensive preclinical safety data. This includes off-target analysis using in silico predictive models further corroborated with biochemical and cellular assessments. These predictions must then be validated clinically during first-in-human studies. Because safety review committees frequently review data between patient enrollments to ensure safety remains the top priority, trial sponsors need to plan for discussions at every step of the process.
The regulatory landscape for genome editing is evolving to meet the pace of technological change. For example, the FDA has issued guidance on genome editing products, emphasizing the need for robust preclinical data, off-target analysis and long-term safety monitoring, as previously noted.
Due to the ethical considerations regarding genome editing, particularly around germline editing, stakeholder transparency is highly critical. Public trust in genome editing depends on clear communication of risks, benefits, and outcomes. This makes open discussions with FDA and other regulatory agencies key for developers - including prompt reporting of adverse events.
The potential for durable disease-modifying effects of genome editing therapies is noteworthy. However, stakeholders also need to address real-world roadblocks to sufficient access, such as pricing, complex manufacturing, and infrastructure requirements. Like other advanced therapies, reimbursement models need to evolve to accommodate these therapies and balance innovation and their "one-and-done" nature with affordability and access.
Rapid scientific advances, thoughtful integration into clinical practice, and expanding global interest are shaping the future of genome editing clinical development. The clinical pipeline is growing, with more than 30 trials underway globally across various genome editing modalities. Soon, the ability to target multiple genes simultaneously could provide a deeper understanding of the genetic variations linked to polygenic (and more prevalent) diseases that affect millions worldwide, such as diabetes and cardiovascular conditions.
Clinical researchers are also evaluating ways to improve delivery systems. These include nonviral nanoparticles, virus-like particles, and antibody-guided delivery to enhance efficiency and specificity and to reduce immunogenicity currently challenging genome editing therapies. Other key innovations include precise editing with novel base and prime editors, epigenome editing, multiplex editing, and targeting cell precursors.
Genome editing is a complicated R&D space with scientific, clinical, regulatory, and commercial hurdles. However, as the field matures, this transformative science can represent a critical paradigm shift in how we understand and treat disease, evolving from symptom management to disease modification.