Why do CRISPR/Cas9 gene editing therapies fail after showing efficacy in rodent models

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CRISPR/Cas9 gene editing therapies often show promising results in rodent models but can encounter several challenges when translated to human clinical settings, leading to failures or reduced efficacy. These challenges include differences in biology between species, immune responses, off-target effects, and delivery mechanisms.

Differences in Biology Between Species

Rodent models, such as mice, are extensively used in preclinical studies due to their genetic, biological, and behavioral similarities to humans. However, there are significant physiological and genetic differences that can affect how results from these models translate to humans. For instance, differences in gene expression, cellular environments, and metabolic processes can lead to varying outcomes in disease manifestation and treatment efficacy 17.

Immune Responses

One of the significant hurdles for CRISPR/Cas9 therapies derived from bacterial systems (like Cas9 from Streptococcus pyogenes) is the human immune system's potential to recognize and attack the CRISPR components as foreign. Many individuals have pre-existing immunity to Cas9 proteins, which can lead to rapid degradation of these proteins or severe immune reactions, reducing the efficacy of the therapy or causing adverse effects 18 8. This immune response can be particularly problematic in direct in vivo applications where the CRISPR components are delivered directly into the body.

Off-Target Effects

CRISPR/Cas9 systems are designed to target specific genetic sequences, but they can sometimes interact with unintended parts of the genome, leading to off-target mutations. These unintended edits can potentially cause harmful genetic disruptions, including tumorigenesis or other genetic disorders 1 2 3 4. While rodent models may not fully manifest the consequences of these off-target effects due to their shorter lifespans or different biological contexts, these effects can become apparent and problematic in long-term human studies.

Delivery Mechanisms

Effective delivery of CRISPR/Cas9 components to the targeted cells in humans remains a significant challenge. While methods like viral vectors are commonly used, they can introduce further complications such as immune responses or insertional mutagenesis. Additionally, ensuring that the editing components are delivered efficiently and persist long enough to have a therapeutic effect without causing toxicity is a critical challenge that often does not fully manifest in rodent models 11 17.

Ethical and Regulatory Challenges

Beyond biological and technical issues, ethical and regulatory concerns also play a role in the translation of CRISPR therapies from rodents to humans. The potential for germline modifications and other permanent genetic alterations raises significant ethical questions and regulatory hurdles that can delay or halt the progress of clinical applications 15 16. In summary, while CRISPR/Cas9 gene editing shows high efficacy in rodent models, its application in human clinical settings faces numerous challenges related to biological differences between species, immune reactions, off-target effects, delivery mechanisms, and ethical considerations. These factors can lead to reduced efficacy or failure of therapies when transitioning from preclinical stages to human trials.

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