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Treatment of CBS deficiency with proteostasis modulators

用蛋白质稳态调节剂治疗 CBS 缺乏症

基本信息

批准号：
10004513
负责人：
WARREN D KRUGER
金额：
$ 46.75万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004513
关键词：
Adult Affect Alleles Amino Acids Back Behavior Binding Bortezomib Complex Cystathionine beta-Synthase Data Disease Dose Drug usage Effectiveness Environment Enzymes FDA approved Genetic Diseases Goals Homocysteine Human Immunoprecipitation Inborn Errors of Metabolism Incidence Individual Kidney Lead Liver Longitudinal Studies Mediating Mental Retardation Metabolism Methionine Missense Mutation Modeling Molecular Chaperones Mus Mutation Osteoporosis Other Genetics Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Plasma Proteasome Inhibition Proteasome Inhibitor Proteins Public Health Serine Serum Supplementation System Techniques Testing Thrombosis Toxic effect Ubiquitin Vitamin B6 Work arimoclomol cancer therapy cancer type dietary restriction enzyme activity experimental study functional restoration humanized mouse lens mouse model multicatalytic endopeptidase complex mutant novel novel strategies polypeptide promoter protein aggregation proteostasis small molecule treatment strategy vitamin therapy

项目摘要

PROJECT SUMMARY/ABSTRACT Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of cellular metabolism. Homocysteine is an intermediary metabolite derived from methionine that can either be recycled back to methionine, or shunted down the transsulfuration pathway by the action of cystathionine beta-synthase (CBS), an enzyme primarily expressed in the liver and kidney. Individuals with mutations in CBS have CBS deficiency, characterized by extreme elevations in plasma total homocysteine (tHcy) and phenotypes including increased incidence of thrombosis, osteoporosis, dislocated lenses, and mental retardation. In healthy adults, tHcy concentration in plasma ranges from 5 to 15 M, but untreated patients with CBS deficiency often have tHcy in excess of 200 M. Current treatment strategies involve dietary restriction and vitamin therapy, but these are only partially effective and do not work in all patients. Over 85% of the described mutations in CBS deficient patients are missense mutations in which a single incorrect amino acid is substituted into the CBS polypeptide. Over the past decade, our lab has developed six different humanized mouse models that each express a different patient-derived mutant human CBS protein using an inducible promoter expressed at high levels in the liver. In all of these models, liver CBS activity is greatly diminished (<5% of wild-type), and serum tHcy is elevated by at least 20-fold. However, the behavior of each mutant CBS protein is not identical, with mutations affecting protein stability, protein aggregation, enzymatic function, or a combination of all three. The decreased protein stability effects of the mutations are mediated via the ubiquitin/proteasome system. Amazingly, treatment of mutant-expressing mice with proteasome inhibitors (PIs) can functionally reverse the effects of a majority of the missense mutations, resulting in large increases in CBS activity in the liver, and in some cases lowering of tHcy to near wild-type levels. PIs are FDA approved drugs for the treatments of certain types of cancer, but have never been studied in the context of inborn errors of metabolism. Our data suggests that low-dose PI treatment may be able to restore sufficient CBS enzyme activity to be phenotypically beneficial, but not have the toxicities associated with the high levels used in cancer therapy. In addition, we have preliminary data that suggests the combination of PIs with other drugs that modulate the cellular proteostasis network, may be useful in increasing the effectiveness of PIs. Thus, the overall goal of the current proposal is to extend these studies and determine if PIs and proteostasis modulators are effective in restoring function to patient-derived CBS alleles. If successful, the experiments described here could lead to novel treatments of CBS deficiency and potentially other genetic diseases associated with missense mutations.

项目总结/摘要先天性代谢缺陷包括一大类涉及细胞代谢紊乱的遗传性疾病。新陈代谢.同型半胱氨酸是甲硫氨酸衍生的中间代谢产物，或通过胱硫醚β-合酶的作用使转硫途径向下分流 (CBS)是一种主要在肝脏和肾脏中表达的酶。CBS突变的个体患有CBS 缺乏症，其特征是血浆总同型半胱氨酸（tHcy）和表型（包括血栓形成、骨质疏松、晶状体脱位和智力迟钝的发病率增加。在健康的成年人中，血浆中tHcy浓度范围为5 - 15 μ M，但未经治疗的CBS缺乏症患者通常 tHcy超过200 μ M。目前的治疗策略包括饮食限制和维生素治疗，但这些药物只是部分有效，并不是对所有患者都有效。在CBS缺陷患者中超过85%的所述突变是错义突变，其中单个突变是错义突变。不正确的氨基酸被替换到CBS多肽中。在过去的十年里，我们的实验室已经开发了六种不同的人源化小鼠模型，其各自表达不同的患者来源的突变人CBS蛋白使用在肝脏中高水平表达的诱导型启动子。在所有这些模型中，肝脏CBS活性是大大降低（<野生型的5%），血清tHcy升高至少20倍。然而，行为每种突变CBS蛋白质的突变是不相同的，突变影响蛋白质稳定性，蛋白质聚集，酶的功能，或所有三个的组合。突变的蛋白质稳定性降低的影响是通过泛素/蛋白酶体系统介导。令人惊讶的是，用蛋白酶体抑制剂（PI）可以在功能上逆转大多数错义突变的作用，导致肝脏中CBS活性大幅增加，在某些情况下，tHcy降低至接近野生型程度. PI是FDA批准的用于治疗某些类型癌症的药物，但从未进行过研究在先天性代谢缺陷的背景下。我们的数据表明，低剂量PI治疗可能能够恢复足够的CBS酶活性，使其在表型上有益，但不具有相关的毒性与癌症治疗中使用的高水平药物相匹配。此外，我们有初步数据表明， PI与调节细胞蛋白质稳态网络的其他药物的组合可用于提高PI的有效性。因此，目前提案的总体目标是扩大这些研究并确定PI和蛋白质稳态调节剂是否能有效恢复患者来源的CBS功能等位基因如果成功的话，这里描述的实验可能会导致CBS缺乏症的新治疗方法，可能与错义突变相关的其他遗传疾病。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy.

DOI：
10.1002/jimd.12437
发表时间：
2021-11
期刊：
Journal of inherited metabolic disease
影响因子：
4.2
作者：
Lee HO;Salami CO;Sondhi D;Kaminsky SM;Crystal RG;Kruger WD
通讯作者：
Kruger WD

In silico and in vivo models for Qatari-specific classical homocystinuria as basis for development of novel therapies.

DOI：
10.1002/humu.23682
发表时间：
2019-03
期刊：
Human mutation
影响因子：
3.9
作者：
Ismail HM;Krishnamoorthy N;Al-Dewik N;Zayed H;Mohamed NA;Giacomo VD;Gupta S;Häberle J;Thöny B;Blom HJ;Kruger WD;Ben-Omran T;Nasrallah GK
通讯作者：
Nasrallah GK

Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis.

DOI：
10.2337/db14-0809
发表时间：
2014-12
期刊：
Diabetes
影响因子：
7.7
作者：
Fang P;Zhang D;Cheng Z;Yan C;Jiang X;Kruger WD;Meng S;Arning E;Bottiglieri T;Choi ET;Han Y;Yang XF;Wang H
通讯作者：
Wang H

Cysteamine revisited: repair of arginine to cysteine mutations.

DOI：
10.1007/s10545-017-0060-4
发表时间：
2017-07
期刊：
Journal of inherited metabolic disease
影响因子：
4.2
作者：
Gallego-Villar L;Hannibal L;Häberle J;Thöny B;Ben-Omran T;Nasrallah GK;Dewik AN;Kruger WD;Blom HJ
通讯作者：
Blom HJ

How to fix a broken protein: restoring function to mutant human cystathionine β-synthase.