Revolutionizing Heart Valve Therapy: A Translational Framework for Combining Decellularized Scaffolds With Genetic Modification

Valvular heart disease (VHD) represents a significant global health challenge, affecting over 2.5% of the population and disproportionately impacting older adults due to age-related degenerative processes. Current treatment options-mechanical and bioprosthetic valves-both present substantial limitations that impact patient quality of life and long-term outcomes. Mechanical valves require lifelong anticoagulation with associated bleeding risks, while bioprosthetic valves suffer from limited durability, typically requiring replacement within 10-15 years. These limitations are particularly problematic for pediatric and young adult populations, who face multiple surgical interventions throughout their lifetime. Decellularized scaffolds have emerged as promising alternatives due to their natural extracellular matrix architecture and potential for recipient cell repopulation and growth, making them especially valuable for pediatric patients. However, these scaffolds face several critical biological challenges that have prevented widespread clinical adoption, including suboptimal recellularization patterns, inflammatory responses, calcification propensity, and structural degradation over time. Recent advances in gene editing technologies, particularly CRISPR-Cas9 and emerging base editing techniques, offer unprecedented opportunities to overcome these limitations by enabling precise molecular-level tissue modifications. These technologies could enhance scaffold biocompatibility, promote favorable cellular responses, prevent calcification, and improve structural integrity. This review explores how combining decellularized scaffold approaches with gene editing techniques could transform heart valve treatment. We examine the potential of this integrated approach to create valve replacements with improved durability and biocompatibility and propose pathways for translating these innovations into clinical practice. The convergence of these technologies holds particular promise for younger patients who would benefit most from heart valves capable of growth and long-term function without repeated surgical interventions.