Stephanie Chan

Pathogenic mechanisms and the prospect of gene therapy for choroideremia.

Introduction: Choroideremia is a rare, X-linked disorder recognized by its specific ocular phenotype as a progressive degenerative retinopathy resulting in blindness. New therapeutic approaches, primarily based on genetic mechanisms, have emerged that aim to prevent the progressive vision loss. Areas covered: This article will review the research that has progressed incrementally over the past two decades from mapping to gene discovery, uncovering the presumed mechanisms triggering the retinopathy to preclinical testing of potential therapies. Expert opinion: While still in an evaluative phase, the introduction of gene replacement as a potential therapy has been greeted with great enthusiasm by patients, advocacy groups and the medical community.

Choroideremia research: Report and perspectives on the second international scientific symposium for choroideremia

ABSTRACT Purpose: To discuss progress in research on choroideremia (CHM) and related retinopathies with special emphasis on gene therapy approaches. Methods: Biomedical and clinical researchers from across the world as well as representatives of the social science research community were convened to the 2nd International Scientific Symposium for Choroideremia in Denver, Colorado in June 2014 to enhance our understanding of CHM and accelerate the translation of research to clinical application for the benefit of those affected by CHM. Results: Pre-clinical research using cell and animal models continues to further our understanding in the pathogenesis of CHM as well as to demonstrate proof-of-concept for gene transfer strategies. With the advent of modern imaging technology, better outcome measures are being defined for upcoming clinical trials. Results from the first gene therapy trial in CHM show promise, with sustained visual improvement over 6 months post-treatment. Current and next-generation gene transfer approaches may make targeted vector delivery possible in the future for CHM and other inherited retinal diseases. Conclusions: While no accepted therapies exist for CHM, promising approaches using viral-vectored gene therapy and cell therapies are entering clinical trials for eye diseases, with gene therapy trials underway for CHM.

Resolving Genetic Test Results for the Patient and the Clinician

F OR THE PATIENT AND CLINICIAN, GENETIC TESTING offers great promise in providing a specific diagnosis, enabling a better understanding of disease, its prognosis, and possible treatment; however, testing may, at the same time, generate uncertainties. Frequently, genetic testing may not be able to distinguish between diseasecausing and benign variants; alternately, variants may be found in a gene other than the gene of interest or generate lists of ‘‘variants of unknown significance.’’ Resolving these unanticipated challenges may be problematic and prove to be a disappointment for the patient, the family, and their clinician. Further, the interpretation of test results may be foreign to the care provider, who then does not know where to turn for help. Consultation with experts may be an important consideration to confirm the clinical diagnosis and then select a test strategy. Posttest consultation with experts in medical genetics on the interpretation of test results may prove instructive but also may not offer either a solution or direction, especially if they are not content experts in heritable eye diseases. Genetic variants identified by clinical genetic testing are typically classified in 1 of 5 categories: pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign. Classification is based on ‘‘criteria using typical types of evidence (eg, population data, computational data, functional data, segregation data),’’ as described in the American College of Medical Geneticists guidelines. Interpretation of results is based on current information available at the time of reporting. Additional information may exist in the future and would obviously not be represented. In other words, genetic variants may be possibly reclassified in the future owing to new/ emerging research on ocular genetic conditions. The following 2 cases are intended to highlight some of the issues around parallel testing for multiple genes with gene panels (Case 1) and a tiered testing approach for candidate genes (Case 2). We also recognize that clinicians may