Gene Therapy in Hutchinson-Gilford Progeria Syndrome

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Project Summary and Abstract Hutchinson-Gilford Progeria Syndrome (HGPS) is an incurable, uniformly fatal disease involving a point mutation in a gene called Lamin A (LMNA). Children develop signs of HGPS typically within the two years after birth and die at a median age of 14, most commonly from progressive atherosclerotic cardiovascular disease. Although the causal mutation in HGPS was identified 18 years ago, no cures for this disease exist. Programmable base editing of DNA now enables the previously unprecedented ability to change single nucleotides in DNA and correct pathogenic mutations with DNA strand breaks. HGPS represents a tractable disease to test base editing, however it remains completely unknown whether this strategy will improve disease phenotypes associated with HGPS. As such, there is a critical need to study how DNA base editing alters the molecular defects driving HGPS in order to determine whether this genome therapy can fulfill its promise to cure disease. Our overall objective in this proposal is develop adenine base editing (ABE) as a treatment strategy for HGPS. Our central hypothesis is that ABE-treatment of adult mice can achieve sufficient editing in aortas to reverse vascular pathology through cell-autonomous effects on survival and clonal proliferation in VSMCs. Our hypothesis is formulated based on newly published and new preliminary data that demonstrate: 1) scarless correction of the pathogenic mutation by ABE in patient fibroblasts and in a humanized mouse model of HGPS; 2) prevention of vascular pathology and recovery of VSMCs at 6 months after ABE treatment of juvenile mice; 3) a significant increase in overall survival of ABE-treated juvenile animals. The rationale for this project is that validation of base editing therapies is needed to determine their potential in treating systemic human diseases. To attain our objectives, we will pursue the following two specific aims: 1) Test whether DNA editing improves vascular pathology in established disease by treating adult HGPS animals at different ages with a single injection of AAV-ABE; 2) Identify the mechanism(s) promoting VSMC recovery after ABE treatment. The overall contribution of this work will be to elucidate how adenine DNA base editing improves phenotypes in HGPS. The central innovation of this proposal is a conceptual shift in therapeutic treatment of HGPs by focusing on correcting the underlying pathogenic mutation in cells and tissues.