Measuring and Understanding Light Sensitivity in Erythropoietic Protoporphyria

测量和了解红细胞生成性原卟啉症的光敏感性

• 批准号: 10641743
• 负责人: Amy Kathryn Dickey
• 金额: $ 17.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641743
• 关键词: Affect; Anemia; Biological Markers; CD34 gene; CRISPR/Cas technology; Cells; Characteristics; Chemicals; Cholelithiasis; Cholestasis; Clinical; Clinical Trials; Clinical Trials Design; Code; Cutaneous; Data; Data Collection; Development; Devices; Digital biomarker; Disease; Dose; Drug Targeting; Environmental Epidemiology; Enzymes; Epidemiology; Erythrocytes; Erythropoietic Protoporphyria; Family; Fluorescence; Fluorometry; General Hospitals; Genes; Genetic; Genotype; Goals; Grant; Heme; In Vitro; Individual; Life; Light; Liver; Liver Failure; Massachusetts; Measurement; Measures; Medicine; Melanins; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolism; Methodology; Methods; Molecular Target; Monitor; Narcotics; Pain; Pathogenicity; Patient Selection; Patients; Photophobia; Photosensitivity; Photosensitivity Disorders; Physicians; Pilot Projects; Plasma; Porphyrias; Porphyrins; Positioning Attribute; Prevention; Quality of life; Reaction; Research; Research Personnel; Resources; Risk; Scientist; Severities; Skin tanning; Standardization; Sunscreening Agents; Surveys; Symptoms; Testing; Text; Training; Ultraviolet Rays; United States Food and Drug Administration; Validation; Variant; afamelanotide; career; chronic liver disease; detector; digital; exome; exome sequencing; genetic analysis; genetic epidemiology; heme biosynthesis; improved; in vitro testing; instructor; iron metabolism; large datasets; light dosimetry; liver transplantation; medical schools; new therapeutic target; novel; novel therapeutics; patient oriented; patient population; patient variability; polygenic risk score; pre-clinical; prevent; protoporphyrin IX; randomized, clinical trials; rare genetic disorder; response; statistics; therapeutic target; tool; trait; treatment effect; treatment response

PROJECT SUMMARY / ABSTRACT Erythropoietic protoporphyria (EPP) is caused by pathogenic variants of the last enzyme of heme biosynthesis, which produces life-long, painful cutaneous sensitivity to light. In EPP, the light-sensitive molecule protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in the plasma and the liver. In addition to photosensitivity, EPP can result in anemia, gallstones, and chronic liver disease, and 2-5% patients develop rapidly progressive cholestatic liver failure that is fatal without liver transplantation. The approval of new therapeutics in EPP has been greatly hindered by the lack of quantitative clinical trial endpoints. While the Food and Drug Administration recently approved one therapy that helps to prevent EPP-related photosensitivity, no disease-modifying therapy is available for EPP. The objective of this study is to develop methods to quantitatively measure light sensitivity in EPP and to understand the genetic basis for differences in light sensitivity among patients. Light sensitivity will be measured by the combination of light dosimetry, transcutaneous PPIX fluorometry, and daily text symptom surveys. The genetic basis for differences in light sensitivity among patients will be characterized by performing whole exome sequencing and a genotyping array in EPP patients possessing the same FECH genotype and large discordances in light sensitivity and/or PPIX level. First, polygenic risk scores that were developed in large datasets will be applied to the genetic data of this selected patient population. Next, disease-modifying coding variants will be identified in the exome sequences, followed by in vitro validation. This project could lead to (1) methods to predict and prevent photosensitivity in EPP thus improving quality of life, (2) quantitative endpoints for clinical trials facilitating the approval of new therapies, and (3) a better understanding of the modulators of light sensitivity in EPP, which could lead to novel therapeutics. This research will be performed by Dr. Amy Dickey, an Instructor of Medicine at Harvard Medical School and Massachusetts General Hospital. She will receive first-rate training in statistics, epidemiology, clinical trial design, and genetic analysis. Furthermore, she will be exceptionally mentored by Dr. David Christiani, an expert in genetic and environmental epidemiology, and co-mentored by Dr. Mark Fleming, an expert in heme metabolism and rare disease genetic analysis. She will perform her research in a world- renowned academic center with all required resources available to her. Dr. Dickey's goal is to become a physician-scientist in patient-oriented porphyria research. This K23 award will provide her with the training and mentorship to achieve independence and apply for her first R01.

项目摘要/摘要

项目成果

Light-Related Cutaneous Symptoms of Erythropoietic Protoporphyria and Associations With Light Sensitivity Measurements.

红细胞生成性原卟啉症的光相关皮肤症状及其与光敏度测量的关联。

• DOI: 10.1001/jamadermatol.2022.5850
• 发表时间: 2023
• 期刊: JAMA dermatology
• 影响因子: 10.9
• 作者: Raef,HayaS;Rebeiz,Lina;Leaf,RebeccaKarp;Hughes,Olivia;Jiang,Paul;ElSeht,Abrahim;Anderson,KarlE;Wheeden,Kristen;Kochevar,Irene;Elmariah,SarinaB;Dickey,AmyK
• 通讯作者: Dickey,AmyK

How I treat erythropoietic protoporphyria and X-linked protoporphyria.

我如何治疗红细胞原质畸形和X连锁原质畸形。

• DOI: 10.1182/blood.2022018688
• 发表时间: 2023-06-15
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Leaf, Rebecca Karp;Dickey, Amy K.
• 通讯作者: Dickey, Amy K.

Prospective observational pilot study of quantitative light dosimetry in erythropoietic protoporphyria.

红细胞生成性原卟啉症定量光剂量测定的前瞻性观察性试点研究。

• DOI: 10.1016/j.jaad.2022.11.036
• 发表时间: 2023
• 期刊: Journal of the American Academy of Dermatology
• 影响因子: 13.8
• 作者: Dickey,AmyK;Rebeiz,Lina;Raef,Haya;Leaf,RebeccaK;Elmariah,Sarina;Naik,Hetanshi;Anderson,Karl;Conley,Jared;Iyasere,Christiana;Zhao,Sophia;Birkenfeld,JudithS;Arroyo-Gallego,Teresa;Wheeden,Kristen;Ducamp,Sarah;Christiani,David
• 通讯作者: Christiani,David