Genotype - phenotype Study of Patients with Plaquenil-induced Retinal Toxicity,

Plaquenil 诱导的视网膜毒性患者的基因型-表型研究，

• 批准号: 9556036
• 负责人: Catherine Cukras
• 金额: $ 2.89万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9556036
• 关键词: Blood specimen; California; Caring; Chloroquine; Clinical; Clinical Data; Collaborations; Computerized Medical Record; Congresses; DNA; DNA Sequence Alteration; Development; Enrollment; Family; Fundus; Genes; Genetic; Genetic Screening; Genotype; Hydroxychloroquine; Individual; Knowledge; Medical; Mutation; Observational Study; Operative Surgical Procedures; Ophthalmic examination and evaluation; Ophthalmologist; Ophthalmology; Other Genetics; Outpatients; Participant; Patient Recruitments; Patients; Pharmaceutical Preparations; Phenotype; Physical Examination; Protocols documentation; Recording of previous events; Recruitment Activity; Retina; Retinal; Sampling; Testing; Time; Toxic effect; United States National Institutes of Health; Universities; Visit; Visual; Visual Fields; field study; genetic analysis; personalized medicine

Plaquenil, or hydroxychloroquine, and its related compound chloroquine, has long been identified to be associated with a retinal toxicity. This toxicity occurs rarely (in the range of 0.5-3.5% of patients on the drug), but, nevertheless, it remains a concern as the toxicity to the retina is mostly, if not wholly, irreversible and the visual sequelae from this toxicity can be devastating. A relationship has been proposed between mutations in the ABCA4 gene and the development of Plaquenil toxicity. If a relationship between ABCA4 mutations, or other genetic mutations, and Plaquenil toxicity is identified this would enable the practice of personalized medicine. The practice of personalized medicine is supported by a bill from the US congress and utilizes the knowledge gained by genetic sequencing to tailor an individuals medical care. It would follow that patients considered for hydroxychloroquine or chloroquine therapy undergo genetic screening for genetic mutations, such as ABCA4 mutations, so that patients who would be exquisitely sensitive to toxic effects of this drug are identified before the treatment is implemented. The objective of this study is to identify genetic mutations, starting with an analysis of ABCA4 mutations, that may be correlated with Plaquenil toxicity and correlate these with the participants phenotypes. This study will recruit 30 patients with Plaquenil-induced retinal toxicity and at least 60 control participants to participate in this study. This is an observational study that requires 1-2 outpatient visits to the NIH Clinical Center or a local ophthalmologists office over a period of time convenient to the participants, not to exceed two years. After gathering a complete medical, family and surgical history, participants will have standard physical and eye examination. The eye examination will include a dilated fundus examination. Non-invasive ophthalmologic testing (e.g., visual field testing, OCT, photos, and autofluorescence) may be performed. Photographs (ophthalmic) will be taken to document the Plaquenil toxicity. Participants will have a 30 cc blood sample drawn for genetic analysis. During this fiscal year, the protocol has gained IRB-approval and recruitment of patients has started. An electronic medical record form has been developed and utilized to store clinical data collected as part of this protocol. The collaboration with Dr. Ayyagaris lab at University of California San Diego will provide the expertise in sequencing and determining the significance of any mutations detected in the patients DNA samples. We have enrolled participants and continue to enroll participants into this study at the NEI.

长期以来，长期以来，已确定plaqueenil或羟基氯喹及其相关的化合物氯喹与视网膜毒性有关。这种毒性很少发生（在0.5-3.5％的药物中范围为0.5-3.5％），但是，它仍然是一个关注点，因为对视网膜的毒性大部分是完全，不可逆的，并且这种毒性的视觉后遗症可能是毁灭性的。 已经提出了ABCA4基因突变与plaquenil毒性的发展之间的关系。 如果确定ABCA4突变或其他遗传突变与plaquenil毒性之间的关系，这将使个性化医学实践。个性化医学的实践得到了美国国会的一项法案的支持，并利用遗传测序获得的知识来量身定制个人医疗服务。随之而来的是，考虑使用羟基氯喹或氯喹疗法的患者进行基因突变的基因筛查，例如ABCA4突变，以便在实施治疗之前鉴定出对这种药物有毒作用非常敏感的患者。 这项研究的目的是从分析ABCA4突变开始，这可能与plaquenil毒性相关，并将这些突变与参与者表型相关。 这项研究将招募30例plaquenil诱导的视网膜毒性，至少60名对照参与者参加这项研究。 这是一项观察性研究，需要1-2次在NIH临床中心或当地眼科医生办公室的门诊就诊，这对参与者来说是方便的，不超过两年。 在收集了完整的医疗，家庭和外科史之后，参与者将进行标准的身体和眼睛检查。眼睛检查将包括扩张的眼底检查。可以进行非侵入性眼科测试（例如，视野测试，OCT，照片和自动荧光）。照片（眼科）将用于记录plaquenil毒性。参与者将有30 cc的血液样本进行遗传分析。 在这个财政年度，该方案获得了IRB批准，并且已经开始招募患者。 已经开发并使用电子病历表来存储作为该协议的一部分收集的临床数据。 与加利福尼亚大学圣地亚哥分校的Ayyagaris博士实验室的合作将提供在测序和确定患者DNA样本中检测到的任何突变的重要性方面的专业知识。 我们已经招募了参与者，并继续在NEI参加这项研究。