Splicing Therapy Comes of Age

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Science  11 Nov 2011:
Vol. 334, Issue 6057, pp. 739
DOI: 10.1126/science.334.6057.739-a

The aging process is not fun, but when it begins decades ahead of schedule, it's tragic. Children with Hutchinson-Gilford progeria syndrome (HGPS) begin to show features of aging before reaching their teens and usually do not survive to their 20s. HGPS is caused by a mutation in the nuclear envelope protein lamin A, which results in the production of a truncated protein, called progerin. Progerin becomes aberrantly tethered to the cell nucleus, thereby disrupting vital nuclear structure and function. To date, most experimental therapies for HGPS have focused on preventing progerin from reaching the nucleus. Two related reports instead now focus on correcting the splicing defect, so that progerin is not produced in the first place. Lopez-Mejia et al. show that splicing factor SRSF1 is a critical participant in the pathogenic splicing mechanism and that its depletion reduces progerin production and corrects the aberrant nuclear phenotype in a cell culture model of HGPS. Osorio et al. show that mice carrying the precise genetic mutation seen in HGPS patients develop the main clinical features of the disorder. Many of the features are ameliorated after systemic delivery of an antisense oligonucleotide that prevents the pathogenic splicing event.

Hum. Mol. Genet. 20, 10.1093/hmg/ddr385 (2011); Sci. Transl. Med. 3, 106ra107 (2011).

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