Corrective GUSB transfer to the canine mucopolysaccharidosis VII cornea using a helper-dependent canine adenovirus vector.

Nicolas Serratrice (1) , Aurelie Cubizolle (1) , Sandy Ibanes (1) , Nadine Mestre-Francés (2) , Neus Bayo-Puxan (1) , Sophie Creyssels (1) , Aurelie Gennetier (1) , Florence Bernex (3) , Jean-Michel Verdier (2) , Mark E Haskins (4) , Guilhem Couderc (5) , François Malecaze (6) , Vasiliki Kalatzis (1) , Eric J Kremer (1)

1 IGMM - Institut de Génétique Moléculaire de Montpellier
2 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
3 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier
4 University of Pennsylvania School of Veterinary Medicine
5 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
6 CPTP - Centre de Physiopathologie Toulouse Purpan

Corneal transparency is maintained, in part, by specialized fibroblasts called keratocytes, which reside in the fibrous lamellae of the stroma. Corneal clouding, a condition that impairs visual acuity, is associated with numerous diseases, including mucopolysaccharidosis (MPS) type VII. MPS VII is due to deficiency in β-glucuronidase (β-glu) enzymatic activity, which leads to accumulation of glycosaminoglycans (GAGs), and secondary accumulation of gangliosides. Here, we tested the efficacy of canine adenovirus type 2 (CAV-2) vectors to transduce keratocyte in vivo in mice and nonhuman primates, and ex vivo in dog and human corneal explants. Following efficacy studies, we asked if we could treat corneal clouding by the injection a helper-dependent (HD) CAV-2 vector (HD-RIGIE) harboring the human cDNA coding for β-glu (GUSB) in the canine MPS VII cornea. β-Glu activity, GAG content, and lysosome morphology and physiopathology were analyzed. We found that HD-RIGIE injections efficiently transduced coxsackievirus adenovirus receptor-expressing keratocytes in the four species and, compared to mock-injected controls, improved the pathology in the canine MPS VII cornea. The key criterion to corrective therapy was the steady controlled release of β-glu and its diffusion throughout the collagen-dense stroma. These data support the continued evaluation of HD CAV-2 vectors to treat diseases affecting corneal keratocytes.

Mots clés: Tissue engineering; Clouding; Primates; Cornea; Mucopolysaccharidosis; Lysosomal storage disorders; β-Glucuronidase; Keratocytes

Domaines: Organes des sens; Ingénierie biomédicale

Nicolas Serratrice, Aurelie Cubizolle, Sandy Ibanes, Nadine Mestre-Francés, Neus Bayo-Puxan, et al.. Corrective GUSB transfer to the canine mucopolysaccharidosis VII cornea using a helper-dependent canine adenovirus vector.. Journal of Controlled Release, 2014, 181, pp.22-31. ⟨10.1016/j.jconrel.2014.02.022⟩. ⟨hal-01104769⟩