Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse.
Proof-of-concept for a successful adeno-associated virus serotype 5 (AAV5)-mediated gene therapy in X-linked juvenile retinoschisis (XLRS) has been demonstrated in an established mouse model for this condition. The initial studies concentrated on early time-points of treatment. In this study, we aimed to explore the consequences of single subretinal injections administered at various stages of more advanced disease. By electroretinogram (ERG), functional improvement in treated versus untreated eyes is found to be significant in retinoschisin-deficient mice injected at the time-points of 15 days (P15), 1 month (PM1), and 2 months (PM2) after birth. In mice treated at 7 months after birth (PM7), an age previously shown to exhibit advanced retinal disease, ERG responses reveal no beneficial effects of vector treatment. Generally, functional rescue is paralleled by sustained retinoschisin expression and significant photoreceptor survival relative to untreated eyes. Quantitative measures of photoreceptors and peanut agglutinin-labeled ribbon synapses demonstrate rescue effects even in mice injected as late as PM7. Taken together, AAV5-mediated gene replacement is beneficial in slowing disease progression in murine XLRS. In addition, we show the effectiveness of rescue efforts even if treatment is delayed until advanced signs of disease have developed. Human XLRS patients might benefit from these findings, which suggest that the effectiveness of treatment appears not to be restricted to the early stages of the disease, and that treatment may prove to be valuable even when administered at more advanced stages.
Janssen
Andreas
A
Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
Min
Seok H
SH
Molday
Laurie L
LL
Tanimoto
Naoyuki
N
Seeliger
Mathias W
MW
Hauswirth
William W
WW
Molday
Robert S
RS
Weber
Bernhard H F
BH
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics*; D018450:Disease Progression; D004596:Electroretinography / Q000379:methods; D005136:Eye Proteins / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041441:Retinoschisis / Q000235:genetics* / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome
D015815:Cell Adhesion Molecules; D005136:Eye Proteins; C491843:RS1 protein, mouse