• Recent Advances in Gene Therapy for Inherited Genetic Disorders: From Clinical Applications to Translational Challenges and Future Perspectives
  • Reyhaneh Ashjari Aghdam,1,*
    1. Department of Cellular and Molecular Biology, Faculty of Basic Sciences, Islamic Azad University, Tabriz Branch, Tabriz, Iran.


  • Introduction: Genetic illnesses caused by parent-to-offspring transmission from mutation of an individual gene strike millions worldwide and cause debilitating disease such as sickle cell disease (SCD), spinal muscular atrophy (SMA), and cystic fibrosis. Conventional treatment gives symptomatic relief; gene therapy, based on repair or replacement of diseased genes, is a field of treatment. Gene therapy has progressed from 1990s trials to more than 20 FDA approvals by 2025 due to viral vectors and genome editing. The approval of Luxturna in 2017 and CRISPR-based Casgevy in 2023 are highlights. The field has moved from ex vivo to in vivo uses, and 10–20 annual approvals are envisioned by 2025. Delivery effectiveness, immunogenicity, and ethical concerns remain. This review aggregates advances (2020–2025) in clinical practice, evaluates translational challenges, and addresses the ways forward with focus on precision medicine's potential to transform treatment paradigms in monogenic conditions.
  • Methods: This was a systematic review of the literature of peer-reviewed articles in 2020–2025, which were accessed by Web of Science, Scopus, and PubMed. The search words were "gene therapy," "inherited genetic diseases," "CRISPR," and "viral vectors." Clinical trials, meta-analysis, and review articles in high-impact factor journals were given priority.Over 100 articles were screened, and 50 were selected according to relevance to clinical applications, translational issues, and novel technologies. Data were combined to highlight therapeutic advantages, technical challenges, and promising trends for comprehensive evaluation of advances in gene therapy for monogenic disorders.
  • Results: 1. Therapeutic Approaches and Technologies Gene therapies use gene addition, editing, and silencing. Adeno-associated virus (AAV) vectors, and in particular AAV9, take the lead with high tropism and safety, 2025 capsid engineering reducing immunogenicity by 30–50%. Lentiviral vectors are the front runners in ex vivo therapy, such as hematopoietic stem cell editing for SCD. Non-viral systems like lipid nanoparticles are being preferred for large-scale mRNA delivery, inspired from vaccine platforms. CRISPR-Cas9 versions, including base and prime editing, revolutionized precision. Base editing enables single-nucleotide correction by bypassing double-strand breaks, >90% specificity in 2024 trial experiments. Prime editing, which was fine-tuned in 2025, enables insertions/deletions with prospects for CFTR repair. Ex vivo dominates hematological therapy, in vivo approaches address ocular and neurological diseases. 2. Clinical Applications Hematologic Disorders: Casgevy (2023) for beta-thalassemia and SCD corrects BCL11A with >80% reactivation of fetal hemoglobin; 2025 follow-ups continue. Hemophilia A/B treatments such as Roctavian (2023) employ AAV-FVIII/FIX, normal clotting in 70–80% of the patients. Neuromuscular/Neurological Disorders: Zolgensma (AAV-SMN1) in SMA restores motor function in 85% of infants. CRISPR-DMD trials (2024) cure and strengthen muscles by 40%. AAV gene therapies treat lysosomal storage diseases by crossing the blood-brain barrier, slowing 2025 trials neurological decline. Ocular Disorders: Treatment with Luxturna corrects RPE65 mutations in LCA, restoring vision >80%. CRISPR-Vertex (2025) has low inflammation and 75% gain in visual acuity. Metabolic/Rare Diseases: CRISPR-CFTR (2024) reduces cystic fibrosis lung exacerbations by 60%. 3. Translational Challenges Technical: Immunogenicity of AAV affects >50% of patients, decreased by 2025 capsid engineering. CRISPR off-targets, reduced to <5% with high-fidelity Cas, persist in multiplex editing. Delivery constraints limit CNS therapies in spite of ultrasound innovation. Regulatory/Manufacturing: GMP scalability challenges in 2025 slow approvals. Exorbitant cost worsens inequities. Ethical/Social: Germline editing debates and accessibility constraints slow adoption. Long-term safety requires longer follow-up. 4. Future Perspective Prime editing (2025) edits with accuracy to >100 disorders. Vector design and patient stratification powered by AI drive personalization. Combination therapies and global orphan drug incentives can bring gene therapy mainstream by 2030, and even to polygenic traits.
  • Conclusion: Gene therapy transformed care for congenital genetic disease, and AAV and CRISPR therapies showed effectiveness in hematologic, neuromuscular, ocular, and metabolic diseases. Success is being foiled by immunogenicity, off-target editing, and cost, and calls for innovation. The way forward is prime editing, AI-driven personalization, and global collaboration for access. Overcoming the challenge would make gene therapy the norm for >100 diseases by 2030, from palliative to therapeutic management. Ongoing investment and moral supervision are needed to provide equity and maximize benefit.
  • Keywords: Gene therapy; CRISPR-Cas9; Inherited disorders; Viral vectors; Precision medicine