2.1.2. Pig Models

A number of *Rho* transgenic pigs have been generated, representing different human mutations: p.Pro23His [24], p.Pro347Leu [25] and p.Pro347Ser [26]. Studies using the p.Pro347Leu pigs showed the development of ectopic cone to rod bipolar cell synapses [27] and also interference with the cone to OFF-bipolar cell connection maturation [28]. The potential contribution of oxidative stress to cone death was demonstrated in the model [29]. The light responses of single rod photoreceptors of p.Pro347Leu and p.Pro347Ser transgenic pigs have been studied by suction pipette recording. The recording revealed protracted recovery of the photoresponse and a progressive reduction in the time to peak of the response with reduced sensitivity. This work suggests that the mutant rhodopsin reaches the outer segmen<sup>t</sup> and that the substitution at Pro347 interferes with inactivation of the activated form of Rho. The resulting hypothesis was that the carboxyl end of Rho may be involved in the binding of rhodopsin kinase. Mutations at Pro347 may reduce the stability of the carboxyl end attachment to rhodopsin kinase, potentially slowing phosphorylation and the subsequent binding of arrestin [30].

The p.Pro23His pig model has been used to study factors associated with cones developing dormancy and whether they can be reactivated. There are stages of retinal degeneration where the degenerating cones lose inner and outer segments. The remaining cell bodies are described as dormant cones. One hypothesis is that a lack of glucose supply to the cones as a result of loss of surrounding rods leads to cone dormancy. Experiments to either introduce rod precursors or to supply glucose to the subretinal space resulted in reactivation of the dormant cones suggesting mechanisms for the treatment of later-stage IRDs [31].
