Abstract
Advances in molecular research have culminated in the development of novel gene-based therapies for inherited retinal diseases. We have recently witnessed several groundbreaking clinical studies that ultimately led to approval of Luxturna, the first gene therapy for an inherited retinal disease. In parallel, international research community has been engaged in conducting gene therapy trials for another more common inherited retinal disease known as choroideremia and with phase III clinical trials now underway, approval of this therapy is poised to follow suit. This chapter discusses new insights into clinical phenotyping and molecular genetic testing in choroideremia with review of molecular mechanisms implicated in its pathogenesis. We provide an update on current gene therapy trials and discuss potential inclusion of female carries in future clinical studies. Alternative molecular therapies are discussed including suitability of CRISPR gene editing, small molecule nonsense suppression therapy and vision restoration strategies in late stage choroideremia.
Highlights
Choroideremia is a rare X-linked recessive inherited retinal disease caused by sequence variations or deletions in the CHM gene which are usually functionally null mutations, leading to deficiency inRab family of GTPases (Rabs) escort protein 1 (REP1) [1,2,3]
In this chapter we review advances in molecular therapies that have resulted in the development of adeno-associated vector (AAV) gene replacement therapy for choroideremia
The reasons for this are not fully understood, but the lack of correlation may be due to the near universal absence of Rab escort protein 1 (REP1) irrespective of the causative mutation that range from single point missense changes to whole gene deletions
Summary
Choroideremia is a rare X-linked recessive inherited retinal disease caused by sequence variations or deletions in the CHM gene which are usually functionally null mutations, leading to deficiency in. REP1 is expressed ubiquitously, in humans choroideremia appears only to affect the retinal pigment epithelium (RPE) layer of the eye, leading to a characteristic clinical phenotype of progressive centripetal retinal degeneration. Recent evidence has shed light on the molecular mechanisms of REP1 contribution to retinal degeneration in choroideremia, describing its essential role in post-translational modification of proteins and in intracellular trafficking of molecules [5]. Since the RPE has an essential role in retinal isomerization in the visual cycle which is more important for rod compared to cone function and rod function is impaired quite early in the disease process. The review discusses current knowledge and progress in molecular mechanisms of choroideremia and the development of emerging potential therapies
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