A silence‑and‑replace gene therapy using AAV9 reported prevention of hereditary spastic paraplegia (HSP) symptoms in recent preclinical studies published in Molecular Therapy. The approach combines RNA silencing of toxic alleles with replacement of functional protein to address both gain‑of‑toxicity and loss‑of‑function disease mechanisms. Researchers from Drexel University and UMass Chan demonstrated phenotypic rescue in relevant models, supporting further development toward clinical translation. The strategy illustrates a growing trend in rare‑disease gene therapy: pairing knockdown with replacement to manage complex genetic pathologies.