Next-Generation CRISPR and Immune Modulation: Advancing Precision Genome Editing Therapies for Genetic Disorders

Dear Colleagues,

The field of precision genome editing for the treatment of genetic diseases has changed considerably over the past decade, as CRISPR technology has evolved from a promising concept to a vital tool in translational medicine. Recent developments emphasize not just the potential of CRISPR-based systems but also the necessity of integrating insights from natural immunity and advancing editing technologies for clinical utility and efficiency.

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and its effector proteins, such as Cas9 and Cas12, which have been developed from prokaryotic adaptive immune systems, are today the basis for the majority of clinical and preclinical genome editing initiatives for monogenic diseases. Through 2025, CRISPR technologies have enabled the correction of previously incurable genetic mutations; the recent delivery of a bespoke, in vivo CRISPR therapy to an infant with carbamoyl phosphate synthetase 1 (CPS1) deficiency marks the beginning of a new era in personalized gene editing. This case of “N-of-1” success reflects the convergence of modular editing tools, accelerated sequencing-to-design workflows, and innovations in the delivery modalities for editing reagents, achieved in a matter of months after diagnosis and before therapeutic intervention. The use of this model is expanding quickly beyond rare metabolic disorders to encompass sickle cell disease, beta thalassemia, and other difficult-to-treat diseases, supported by major regulatory breakthroughs like FDA approval for conventional and next-generation CRISPR-based therapeutic approaches.

At the heart of these innovations is a drive towards increased precision. Classic CRISPR/Cas9 generates double-strand breaks, providing potent gene disruption and correction at the expense of off-target mutations and unpredictable genomic rearrangements. More recent technologies—base editors and prime editors—permit single-nucleotide conversions and exact insertion/deletion corrections without breaks, severely curtailing unwanted effects and making the correction of nearly all pathogenic variants possible. These systems are molecular pencils and word processors, facilitating the effortless “search-and-replace” of genetic instructions. Early-stage clinical data using these tools are especially encouraging for single-base diseases, offering strong efficacy and safety profiles.

The intersection of genome editing with innate immunity presents challenges as well as opportunities. Cells' built-in sensors for nucleic acids can limit the uptake, stability, and fidelity of genome editing reagents, increasing the potential for immune-mediated toxicities or diminished editing efficiencies. Recent research, however, has demonstrated the ability to manipulate innate immune signaling, tune delivery vectors, and even edit mature innate immune and myeloid cells for immunotherapy or tolerance induction. New delivery modalities—stretching from non-viral nanoparticles to engineered viral vectors with immune-evasive coats—are breaking long-standing bottlenecks in cell-type specificity and in vivo applicability.

A further domain in the realm of precision editing is multiplex editing, which facilitates the concurrent manipulation of multiple DNA sequences without triggering a DNA damage response or undermining genomic integrity. Advances in the tools that utilize Cas12 alongside enhanced guide RNA design now present the opportunity to modify several genomic loci simultaneously, thereby expanding the potential for addressing polygenic diseases and applications within synthetic biology.

This being said, some difficulties encompass mosaicism in germline editing (ethically limited) and immune reaction to Cas proteins, originating from bacterial immunity. To overcome these difficulties, some improvements are being made: Anti-CRISPR proteins, found in bacteriophages, are being designed to temporally control Cas activity, reducing off-target effects. Furthermore, machine learning models, trained on extensive genomic data, foresee and avert off-target dangers, leading to safer therapeutic results. In the future, multiplex CRISPR (e.g., CRISPR-Cas12a for arrayed editing) aims to target polygenic diseases such as cardiomyopathy. AI-driven sgRNA design (e.g., DeepCRISPR, 2024 versions) maximizes efficacy, while in utero editing is demonstrating potential in preclinical models for congenital diseases. CRISPR's path from innate immunity to precision therapy highlights its ability to cure genetic illnesses, with current advancements set to enhance its scope. This Special Issue invites the submission of original articles or comprehensive reviews focusing on CRISPR/ Cas9, genome editing, monogenic disorders, and AI-driven CRISPR.

Dr. Sukanta Jash
Guest Editor

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• CRISPR/Cas9
• base editors
• prime editors
• innate immunity
• genome editing
• off-target effects
• delivery vectors
• monogenic disorders
• multiplex editing
• AI-driven CRISPR