Journal of Rare Disorders: Diagnosis & Therapy

Description

Rare monogenic disorders, caused by mutations in a single gene, present unique challenges in medicine due to their rarity, severity and often limited treatment options. In recent years, advancements in genetic engineering, particularly gene editing, have opened new frontiers in addressing these conditions. With the advent of precise gene-editing tools of correcting genetic mutations at their source has moved from theoretical to practical application. This article examines the potential of gene editing as a therapeutic strategy for rare monogenic disorders, highlighting its promise, challenges and future directions. Monogenic disorders stem from mutations in a single gene and can manifest as autosomal dominant, autosomal recessive, or X-linked conditions. Examples include cystic fibrosis, sickle cell anemia, Huntington's disease and Duchenne muscular dystrophy. Although individually rare, collectively, monogenic disorders affect millions worldwide. These conditions often manifest early in life, significantly impacting quality of life. Current treatment approaches, such as enzyme replacement therapy or symptomatic management, fail to address the root cause of the disease. This underscores the critical need for innovative therapies capable of directly targeting and correcting genetic defects. Derived from bacterial immune systems, uses a guide RNA to target specific DNA sequences, enabling the Cas9 enzyme to cut the DNA at precise locations. This process triggers cellular repair mechanisms, which can be harnessed to introduce or correct genetic material. Consist of custom-designed proteins that bind to specific DNA sequences, coupled with a nuclease that cuts the DNA. Although more labor-intensive to design than offer high specificity and reduced off-target effects. Zinc finger domains to bind DNA and a nuclease to induce cuts.

Clinical advances

Several innovative studies and clinical trials have demonstrated the potential of gene editing for monogenic disorders: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based therapies like CTX001 have shown remarkable success in early-phase clinical trials, with patients achieving sustained production of healthy hemoglobin.

Researchers have used in vivo CRISPR-Cas9 editing to correct mutations in the CEP290 gene, restoring vision in animal models and advancing toward human trials. Gene-editing approaches targeting the SMN1 gene are under investigation, offering hope for a condition with limited treatment options. Efficiently delivering gene-editing components to target tissues remains a major hurdle. Viral vectors and non-viral methods are being optimized for safety and efficacy. Unintended edits in non-target regions of the genome could lead to harmful consequences, including cancer. Advanced techniques like high-fidelity and base editing aim to minimize these risks. The immune system may recognize gene-editing components as foreign, reducing efficacy and posing safety risks. Strategies to evade immune detection are under development. Gene-editing therapies are resourceintensive, making them expensive and inaccessible to many patients. Efforts are needed to reduce costs and ensure equitable access.

Ethical concerns

Gene editing raises ethical questions, particularly regarding germline editing, which involves changes that can be inherited by future generations. While somatic editing is widely accepted, germline editing remains controversial due to potential unintended consequences and societal implications. Innovations like prime editing and variants promise greater accuracy and fewer side effects. Developing safer, more efficient delivery mechanisms will expand the range of treatable conditions. While current efforts focus on specific diseases, expanding gene editing to polygenic and complex disorders is a long-term goal. Clear guidelines and ethical oversight will be vital for the safe and responsible development of gene-editing therapies. Gene editing represents a paradigm shift in the treatment of rare monogenic disorders, offering hope for conditions previously deemed untreatable. By addressing the root cause of genetic diseases, this transformative technology has the potential to improve the lives of millions. However, realizing its full potential will require overcoming technical, ethical and logistical challenges. As science and medicine progress, the dream of eradicating rare genetic disorders is closer to becoming a reality, ushering in a new era of precision medicine.