Downregulation of apoptosis-inducing factor in Harlequin mice induces progressive and severe optic atrophy which is durably prevented by AAV2-AIF1 gene therapy.

The Harlequin mutant mouse, characterized by loss of function of apoptosis-inducing factor, represents a reliable genetic model that resembles pathologies caused by human mitochondrial complex I deficiency. Therefore, we extensively characterized the retinal morphology and function of Harlequin mice during the course of neuronal cell death leading to blindness, with the aim of preventing optic atrophy. Retinas and optic nerves from these mice showed an isolated respiratory chain complex I defect correlated with retinal ganglion cell loss, optic atrophy, glial and microglial cell activation. All of these changes led to irreversible vision loss. In control mice, retinas AIF1 messenger RNA was 2.3-fold more abundant than AIF2, both messenger RNAs being sorted to the mitochondrial surface. In Harlequin mouse retinas, there was a 96% decrease of both AIF1 and AIF2 messenger RNA steady-state levels. We attained substantial and long-lasting protection of retinal ganglion cell and optic nerve integrity, the preservation of complex I function in optic nerves, as well as the prevention of glial and microglial responses after intravitreal administration of an AAV2 vector containing the full-length open reading frame and the 3' untranslated region of the AIF1 gene. Therefore, we demonstrate that gene therapy for mitochondrial diseases due to mutations in nuclear DNA can be achieved, so long as the 'therapeutic gene' permits the accurate cellular localization of the corresponding messenger RNA.