Rational Development of Bioengineered Factor IX Variants for Hemophilia B Therapy

用于治疗 B 型血友病的生物工程因子 IX 变体的合理开发

基本信息

批准号：
10083221
负责人：
Ben J Samelson-Jones
金额：
$ 15.94万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-05 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083221
关键词：
Active Sites Address Advisory Committees Amino Acid Substitution Amino Acids Award Binding Binding Sites Biochemical Biochemistry Biological Biological Process Biomedical Engineering Blood Circulation Blood Coagulation Disorders Blood Coagulation Factor Capsid Cells Cellular Immunology Child Coagulation Process Color Databases Development Development Plans Dose Drug Kinetics Epitopes Factor IX Factor VIIIa Factor X Gene Proteins Gene therapy trial Goals Hemophilia A Hemophilia B Hemorrhage Hemostatic Agents Hemostatic function Hot Spot Hyperactivity Immune response Inherited Injury Intravenous infusion procedures Investigation K-Series Research Career Programs Knowledge Laboratories Letters Link Mentors Missense Mutation Molecular Molecular Immunology Mus Mutagenesis Mutation Peptide Hydrolases Phase Physicians Physiological Positioning Attribute Proteins Recombinants Regulation Research Role Safety Scientist Series Site Structure Testing Text Therapeutic Training Training Programs Translations Triad Acrylic Resin Variant Viral Genes Work adeno-associated viral vector base career career development cofactor congenital blood disorder cost early phase clinical trial enhancing factor experience gene therapy immunogenic immunogenicity improved in vivo insight mouse model neoantigens novel novel therapeutics patient population skills standard of care success therapeutic development therapeutic gene thrombogenesis thrombotic translational study

项目摘要

PROJECT SUMMARY This K08 Career Development Award details a four-year training program to advance Dr. Samelson-Jones’ career goal of becoming an independent physician-scientist focused on leveraging molecular insights of biological processes into new therapeutics for children with congenital blood disorders. During the award period, Dr. Samelson-Jones will continue developing his expertise in coagulation biochemistry, acquire new scientific skills, deepen his knowledge of molecular and cellular immunology, and advance his translational capabilities. Under the guidance of his mentor, Dr. Mortimer Ponz, and co-mentor, Dr. Valder Arruda, these training objectives will be met by a combination of didactic course work, participation in seminar series, research experience, and mentoring by his advisory committee. His advisory committee is composed of world- renowned scientists with extensive mentoring experience and diverse and complementary scientific expertise including Drs. Sriram Krishnaswamy, Rodney Camire, and Michael Milone. The scientific proposal is aimed at addressing the current limitations of therapies for hemophilia B (HB). HB is due to an inheritable deficiency in coagulation Factor IX (FIX) activity. The current standard-of-care in the developed world for HB is to replace the missing FIX with intravenous infusions, but there are also several ongoing early phase gene therapy trials. Recently, it was demonstrated that the incorporation of the hyperactive FIX variant, R338L into a gene therapeutic partially mitigates previously identified efficacy limitations without additional safety concerns. This result emphasizes the potential of hyperactive FIX variants as gene, protein, or cell therapeutics for HB. Dr. Samelson-Jones’ proposal focuses on identifying and carefully characterizing new FIX variants with increased activity. He has developed a rational strategy to identify new hyperactive FIX variants by specifically testing substitutions at positions that are 1) evolutionarily conserved; 2) absent from the HB database; and 3) structurally important for protease function. This approach has already identified several new hyperactive FIX variants. The activity of one new variant, FIX-LK, exceeds the activity of FIX-R338L by over 2 fold. In Aim 1, additional FIX variants will be identified and biochemically characterized with recombinant FIX protein. The in vivo efficacy of the best performing new variant will be comprehensively evaluated as protein and gene therapeutics in a HB mouse model in Aim 2. In Aim 3, the safety of the most promising new variants is assessed. The immunogenicity and thrombogenicity of new FIX variants is compared to wild-type FIX after provocative challenges in novel HB mouse models.

项目概要 K08 职业发展奖详细介绍了一项为期四年的培训计划，以提升 Samelson-Jones 博士的能力成为一名独立的医师科学家的职业目标，专注于利用分子洞察力获奖期间将生物过程转化为治疗先天性血液疾病儿童的新疗法。在此期间，Samelson-Jones 博士将继续发展他在凝血生物化学方面的专业知识，获取新的知识科学技能，加深他对分子和细胞免疫学的了解，并推进他的转化在他的导师 Mortimer Ponz 博士和合作导师 Valder Arruda 博士的指导下，这些能力。培训目标将通过教学课程工作、参加系列研讨会、研究经验，以及他的顾问委员会的指导。他的顾问委员会由世界各地的专家组成。拥有丰富指导经验和多样化且互补的科学专业知识的著名科学家该科学提案的目标是：Sriram Krishnaswamy、Rodney Camire 和 Michael Milone。解决目前 B 型血友病 (HB) 治疗的局限性是由于遗传性缺陷所致。凝血因子 IX (FIX) 活性是发达国家目前的 HB 治疗标准。静脉输注缺失的 FIX，但也有几项正在进行的早期基因治疗试验。最近，研究表明，过度活跃的 FIX 变体 R338L 并入基因治疗部分缓解了先前确定的疗效限制，且没有额外的安全问题。结果强调了高度活跃的 FIX 变体作为 HB 的基因、蛋白质或细胞疗法的潜力。 Samelson-Jones 的提案侧重于识别和仔细表征新的 FIX 变体，增加他制定了一种合理的策略，通过专门测试来识别新的过度活跃的 FIX 变体。 1) 进化上保守的位置的替换；2) HB 数据库中不存在的位置；以及这种方法对于蛋白酶功能具有重要的结构意义，已经鉴定出几种新的高度活跃的 FIX。在 Aim 1 中，一种新变体 FIX-LK 的活性超过 FIX-R338L 的活性 2 倍以上。其他 FIX 变体将通过重组 FIX 蛋白进行鉴定和生化表征。表现最佳的新变体的体内功效将根据蛋白质和基因进行综合评估目标 2 中 HB 小鼠模型中的治疗方法。目标 3 中，最有前途的新变体的安全性是评估新 FIX 变体与野生型 FIX 的免疫原性和血栓形成性。新型 HB 小鼠模型中的挑衅性挑战。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activated protein C has a regulatory role in factor VIII function.

活化的蛋白 C 对因子 VIII 功能具有调节作用。

DOI：
发表时间：
2021
期刊：
影响因子：
20.3
作者：
Wilhelm, Amelia R;Parsons, Nicole A;Samelson;Davidson, Robert J;Esmon, Charles T;Camire, Rodney M;George, Lindsey A
通讯作者：
George, Lindsey A

Gene Therapy for Inherited Bleeding Disorders.

遗传性出血性疾病的基因治疗。

DOI：
发表时间：
2021-03
期刊：
影响因子：
5.7
作者：
Arruda, Valder R;Weber, Jesse;Samelson
通讯作者：
Samelson

Adeno-Associated Virus Gene Therapy for Hemophilia.

血友病的腺相关病毒基因治疗。

DOI：
发表时间：
2023-01-27
期刊：
影响因子：
0
作者：
Samelson;George, Lindsey A
通讯作者：
George, Lindsey A

Digital haemophilia: Insights into the use of social media for haemophilia care, research and advocacy.

数字血友病：深入了解社交媒体在血友病护理、研究和宣传中的使用。

DOI：
发表时间：
2022-03
期刊：
影响因子：
0
作者：
Chen, Robert;Muralidharan, Kavitha;Samelson
通讯作者：
Samelson

Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants.

对凝血因子 IX Padua 和其他高比活性变体的进化见解。

DOI：
10.1182/bloodadvances.2019000405
发表时间：
2021-03-09
期刊：
Blood advances
影响因子：
7.5
作者：
B. Samelson;Jonathan D. Finn;L. Raffini;E. Merricks;R. Camire;T. Nichols;V. Arruda
通讯作者：
V. Arruda