The RPGRIP1-deficient dog, a promising canine model for gene therapy.
OBJECTIVE
To evaluate the RPGRIP1-deficient miniature longhaired dachshund (MLHD) dog as a potential candidate for gene therapy.


METHODS
Six RPGRIP1-deficient MLHD dogs from our dog colony have been observed for two years using a variety of noninvasive procedures. These included bilateral full-field electroretinograms (ERG) to evaluate retinal function, fundus photographs to evaluate retinal vascularization, and optical coherence tomographs (OCT) to evaluate retinal thickness. We also performed histological examination of hematoxylin- and eosin-stained retinal sections as well as sections labeled in situ by the terminal dUTP nick end labeling (TUNEL) method.


RESULTS
ERG findings showed that as early as 2 months of age, cone function was lost while rod function was preserved. However, by 9 months of age, both cone and rod functions could not be detected. Functional visual assessment based on the ability to avoid obstacles showed that vision was retained up to the age of 11 months. Both OCT and histopathology studies revealed a progressive thinning of the outer nuclear layer (ONL) over the first 2 years of age. TUNEL labeling identified apoptotic photoreceptor cell death as the cause of this thinning of the ONL.


CONCLUSIONS
A treatment strategy should consist in initiating gene therapy as early as possible after birth to prevent or delay the loss of rod function. In the MLHD, successful subretinal delivery of a therapeutic vector is feasible at 2 months of age and may prevent or delay the loss of rod function.
Lhériteau
Elsa
E
INSERM UMR 649, CHU-Hôtel Dieu, Nantes, France.
Libeau
Lyse
L
Stieger
Knut
K
Deschamps
Jack-Yves
JY
Mendes-Madeira
Alexandra
A
Provost
Nathalie
N
Lemoine
Francoise
F
Mellersh
Cathryn
C
Ellinwood
N Matthew
NM
Cherel
Yan
Y
Moullier
Philippe
P
Rolling
Fabienne
F
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001766:Blindness / Q000235:genetics / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D004285:Dogs / Q000235:genetics*; D004596:Electroretinography; D005455:Fluorescent Antibody Technique; D005654:Fundus Oculi; D015316:Genetic Therapy; D020287:In Situ Nick-End Labeling; D016011:Normal Distribution; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels; D041623:Tomography, Optical Coherence; D014785:Vision, Ocular / Q000235:genetics
D011506:Proteins