Mendes, H.F.C.P.; (2007) Pharmacological therapies for rhodopsin retinitis pigmentosa. Doctoral thesis , University of London.

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Abstract

Mutations in the visual pigment protein rod opsin are the most common cause of autosomal dominant retinitis pigmentosa (ADRP) and the majority of these mutations lead to the misfolding of the protein. Patients with ADRP experience progressive loss of vision leading to blindness and at the moment no effective therapy is available. In this study I have developed a cellular model that can mimic the gain-of function and dominant-negative disease mechanisms in rhodopsin ADRP patients. Whereas wild-type rod opsin translocated to the plasma membrane of the cells, P23H mutant rod opsin misfolded was retained in the ER and accumulated in intracellular inclusions. Several pharmacological compounds were tested in this model. The retinoids 9-c/s-retinal and 11-c/s-retinal reduced inclusion incidence, alleviated cell death and promoted the translocation of the mutant protein to the plasma membrane in cells expressing P23H rod opsin. In cells co-expressing wild-type and P23H rod opsin these compounds restored the normal processing of the wild-type protein, indicating an alleviation of the dominant-negative mechanism of cell death. Chemical chaperones reduced inclusion incidence and cell death but, unlike retinoids, did not to promote the translocation of the mutant protein and did not alleviate the dominant-negative interaction between wild-type and P23H rod opsin. Heat shock protein inducers were also used. Some of these drugs reduced inclusion incidence and cell death in P23H cells. In addition, one partially promoted the translocation of the mutant protein and partially suppressed the dominant-negative mechanism of cell death induced by the mutant protein. Treatment with other compounds such as autophagy inducers also reduced inclusion incidence and cell death in cells expressing P23H rod opsin. These data have identified a range of compounds that demonstrate the 'proof of principle' that some of the gain of function and dominant-negative properties of mutant misfolded rod opsin can be manipulated. The efficacy of these compounds must be established in animal models prior to translation into the clinic.

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