Human Biochemical Genetics

人类生化遗传学

• 批准号: 7147968
• 负责人: William Allen Gahl
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH 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/7147968
• 关键词: Hartnup disease; albinism; clinical research; cornea disorder; cysteamine; cystinosis; diagnosis design /evaluation; diagnostic tests; disease /disorder model; eye disorder chemotherapy; genetic susceptibility; human genetic material tag; human subject; human therapy evaluation; human tissue; inborn metabolism disorder; intracellular transport; laboratory mouse; molecular genetics; molecular pathology; orphan disease /drug; patient oriented research; platelet disorder; tissue /cell culture

The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for neglected groups of patients. 1. Members of the Section admitted approximately 85 individuals with cystinosis as inpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, swallowing ability, and abnormalities of the posterior segment of the eye. They also reported idiopathic intracranial hypertension as a complication of cystinosis and, in collaboration with colleagues in the National Eye Institute, provided cysteamine eyedrops to patients suffering from photophobia due to corneal crystal accumulation. The group continues to work to bring cysteamine eyedrops to New Drug Approval by the FDA. 2. The Section has intensified its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In a pilot study, seven patients achieved a reduction of approximately 95% of their homogentisic acid production by taking 2 mg per day of the drug nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid. The Section has now initiated a randomized clinical trial of nitisinone in alkaptonuria, using hip range of motion as the primary outcome parameter. An Investigational New Drug (IND) exemption has been granted by the FDA for this study. 3. The Section has become a center for investigating the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of melanosomes and platelet dense bodies. There are 7 genetic subtypes of this disease, and the Section has cared for more than 140 affected individuals. In basic studies, members of the Section and their collaborators described abnormal protein trafficking in HPS-1, HPS-2, and HPS-3 melanocytes and an HPS-like disease in mice due to deficiency of a transporter regulating pheomelanin production. The Section also reported a quantitative real-time PCR method to detect hemizygosity in an HPS-1 patient, and demonstrated that the HPS3 protein interacts with clathrin; this important finding explains the function of HPS3 in intracellular trafficking. In clinical studies, the group and colleagues described the first successful lung transplantation in an HPS patient, the specific eye movement abnormalities associated with HPS, and the granulomatous colitis of HPS in relation to particular subtypes. Physicians in the Section have initiated a randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. The outcome parameter is change in forced vital capacity. An IND has been obtained, and enrollment is underway. The group continues to define the natural history of clinical involvement in HPS, and to perform cell biological studies of the movement of intracellular vesicles. 4. The Section is performing linkage studies of Gray Platelet Syndrome, a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. 5. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis to define the natural history and determine outcome parameters for future therapeutic intervention. Twenty-five patients have been evaluated in this study, and the Section, along with the Office of Rare Diseases, sponsored a workshop on ARPKD/CHF attended by national authorities in the field. 6. A new clinical protocol investigates the natural history of Hutchinson-Gilford Progeria syndrome. To date, 10 patients with this premature aging syndrome have been enrolled, and therapeutic trials are under consideration. 7. Several patients were seen with Chediak-Higashi disease, a disorder of large intracellular granules and a tendency toward fatal infections. The Section described one affected child in detail, identifying the causative mutations in the LYST gene and providing genotype-phenotype correlation.

人类生化遗传学研究部分选择了代谢的先天错误，以洞悉细胞机制，并照顾被忽视的患者组。 1。本节的成员接纳了大约85名膀胱变性的人作为NIH临床研究中心的住院患者，记录了口服cysteamine治疗在生长，肾功能，吞咽能力和眼后段异常方面的有益作用。他们还报道了特发性颅内高血压是膀胱变性的并发症，并与国家眼科研究所的同事合作，为由于角膜晶体积累而遭受恐惧症的患者提供了cysteamine eiedrops。该小组继续致力于将Cysteamine Eyedrops带到FDA的新药批准。 2。该部分加强了其对烷酸核尿尿症的研究，这是由于均匀剂量1,2-二加氧酶的缺乏而导致同叶酸的积累障碍。在一项试点研究中，七名患者每天服用2毫克的耐药蛋白酮，降低了大约95％的均匀酸产生，这是一种强大的酶抑制剂，可产生同质酸。该节现在使用髋关节运动范围作为主要结果参数，开始了一项在烷酸核尿症中硝酸盐中的硝酸盐的随机临床试验。 FDA已批准了一项调查新药（IND）豁免。 3。该部分已成为研究Hermansky-Pudlak综合征（HPS）的临床和基本方面的中心，Hermansky-Pudlak综合征（HPS）是一种罕见的眼皮白化病和由于异常形成黑素体和血小板致密体而出血。该疾病有7种遗传亚型，该部分已经照顾了140多个受影响的个体。在基础研究中，该部分及其合作者的成员描述了HPS-1，HPS-2和HPS-3黑色素细胞中的异常蛋白质运输，并且由于调节植物素产生的转运蛋白的缺乏，小鼠中小鼠的HPS样疾病。本节还报道了一种定量的实时PCR方法，可检测HPS-1患者的半合子，并证明HPS3蛋白与网格蛋白相互作用。这一重要发现解释了HPS3在细胞内贩运中的功能。在临床研究中，小组及其同事描述了HPS患者的第一次成功肺移植，与HPS相关的特定眼运动异常以及与特定亚型有关的HPS肉芽肿性结肠炎。本节中的医师已开始对抗纤维化剂Pirfenidone的随机，安慰剂对照的临床试验，以对抗HPS的致命肺纤维化。结果参数是强制生命力的变化。已经获得了IND，并且正在进行注册。该小组继续定义HPS临床参与的自然历史，并对细胞内囊泡运动进行细胞生物学研究。 4。该部分正在进行灰血小板综合征的连锁研究，该疾病中缺乏血小板α颗粒，患者患有出血症状。 5。正在进行的临床方案研究常染色体隐性多囊肾脏疾病和先天肝纤维化，以定义自然史并确定未来治疗干预的结果参数。在这项研究中对25例患者进行了评估，该部分以及罕见疾病办公室赞助了该领域国家当局参加的ARPKD/CHF的研讨会。 6。一项新的临床方案调查了哈钦森 - 吉尔福德富豪综合症的自然史。迄今为止，已经招募了10例此早熟综合征的患者，并且正在考虑治疗试验。 7。有几名患者患有Chediak-Higashi病，一种大细胞内颗粒的疾病以及致命感染的趋势。本节描述了一个受影响的儿童，鉴定了LYST基因中的因果突变并提供基因型 - 表型相关性。