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.

人类生化遗传学部分的研究选择了先天性代谢缺陷，以深入了解细胞机制和对被忽视的患者群体的护理。 1. 该部门的成员将大约 85 名胱氨酸中毒患者收治至 NIH 临床研究中心，记录了口服半胱胺治疗对生长、肾功能、吞咽能力和眼后段异常的有益效果。他们还报告了特发性颅内高压是胱氨酸中毒的并发症，并与国家眼科研究所的同事合作，为因角膜晶体积聚而患有畏光的患者提供了半胱胺滴眼液。该小组继续努力使半胱胺滴眼剂获得 FDA 的新药批准。 2. 该科加强了对尿黑酸尿症的调查，黑尿酸尿症是一种由于尿黑酸1,2-双加氧酶缺乏而导致尿黑酸蓄积的疾病。在一项初步研究中，7 名患者通过每天服用 2 毫克尼替西农（一种产生尿黑酸的酶的强效抑制剂），使尿黑酸的产生量减少了约 95%。该科现已启动一项尼替西农治疗黑酸尿症的随机临床试验，使用髋关节活动范围作为主要结果参数。 FDA 已授予本研究研究性新药 (IND) 豁免。 3. 该科已成为研究赫曼斯基-普德拉克综合征（HPS）临床和基础方面的中心，这是一种罕见的眼皮肤白化病和由于黑素体和血小板致密体形成异常而出血的疾病。这种疾病有 7 种遗传亚型，该科已照顾了 140 多名受影响的个体。在基础研究中，该部门的成员及其合作者描述了 HPS-1、HPS-2 和 HPS-3 黑素细胞中的异常蛋白质运输以及由于缺乏调节褐黑素产生的转运蛋白而导致的小鼠 HPS 样疾病。该科还报告了一种定量实时PCR方法，用于检测HPS-1患者的半合子性，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 在细胞内运输中的功能。在临床研究中，该小组和同事描述了首次成功的 HPS 患者肺移植、与 HPS 相关的特定眼球运动异常，以及与特定亚型相关的 HPS 肉芽肿性结肠炎。该科的医生发起了一项抗纤维化药物吡非尼酮的随机、安慰剂对照临床试验，以对抗 HPS 的致命性肺纤维化。结果参数是用力肺活量的变化。 IND 已获得，注册正在进行中。该小组继续定义 HPS 临床参与的自然史，并对细胞内囊泡运动进行细胞生物学研究。 4. 该科正在开展灰血小板综合征的关联研究，灰血小板综合征是一种血小板α颗粒缺失且患者患有出血素质的疾病。 5. 一项正在进行的临床方案研究常染色体隐性多囊肾病和先天性肝纤维化，以确定自然史并确定未来治疗干预的结果参数。这项研究对 25 名患者进行了评估，该科与罕见病办公室共同主办了一次有关 ARPKD/CHF 的研讨会，该领域的国家当局参加了研讨会。 6. 一项新的临床方案调查了 Hutchinson-Gilford 早衰综合症的自然史。迄今为止，已有 10 名患有这种早衰综合症的患者入组，治疗试验正在考虑中。 7. 几名患者被发现患有 Chediak-Higashi 病，这是一种大细胞内颗粒疾病，有致命感染的倾向。该部分详细描述了一名受影响的儿童，确定了 LYST 基因的致病突变并提供了基因型与表型的相关性。