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Defects in the photoreceptor-specific gene encoding aryl hydrocarbon receptor-interacting protein-like 1 ( AIPL1 ) are clinically heterogeneous and present as Leber Congenital Amaurosis, the severest form of early-onset retinal dystrophy and milder forms of retinal dystrophies such as juvenile retinitis pigmentosa and dominant cone-rod dystrophy. [Perrault, I., Rozet, J.M., Gerber, S., Ghazi, I., Leowski, C., Ducroq, D., Souied, E., Dufier, J.L., Munnich, A. and Kaplan, J. (1999) Leber congenital amaurosis.  Mol. Genet. Metab .,  68,  200–208.] Although not yet fully elucidated, AIPL1 is likely to function as a specialized chaperone for rod phosphodiesterase (PDE). We evaluate whether AAV-mediated gene replacement therapy is able to improve photoreceptor function and survival in retinal degeneration associated with  AIPL1  defects. We used two mouse models of  AIPL1  deficiency simulating three different rates of photoreceptor degeneration. The  Aipl1  hypomorphic (h/h) mouse has reduced Aipl1 levels and a relatively slow degeneration. Under light acceleration, the rate of degeneration in the  Aipl1  h/h mouse is increased by 2–3-fold. The  Aipl1 −/− mouse has no functional Aipl1 and has a very rapid retinal degeneration. To treat the different rates of degeneration, two pseudotypes of recombinant adeno-associated virus (AAV) exhibiting different transduction kinetics are used for gene transfer. We demonstrate restoration of cellular function and preservation of photoreceptor cells and retinal function in  Aipl1  h/h mice following gene replacement therapy using an AAV2/2 vector and in the light accelerated  Aipl1  h/h model and  Aipl1 −/− mice using an AAV2/8 vector. We have thus established the potential of gene replacement therapy in varying rates of degeneration that reflect the clinical spectrum of disease. This is the first gene replacement study to report long-term rescue of a photoreceptor-specific defect and to demonstrate effective rescue of a rapid photoreceptor degeneration.

human molecular genetics

Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in  AIPL1 : effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors