Development of highly efficient factor VIII mini-gene therapy

开发高效因子VIII小基因疗法

• 批准号: 10340474
• 负责人: WEIDONG XIAO
• 金额: $ 48.1万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10340474
• 关键词: Development; highly; efficient; factor; VIII

 DESCRIPTION (provided by applicant): Approximately one in 5000 males in human population suffers from coagulation disorder, hemophilia A. This disease is primarily caused by deficiency in the factor VIII gene located in the X-chromosome and is difficult to treat by conventional medicine. Current treatment of hemophilia A by intravenous infusion of factor VIII concentrates is very costly and has a potential side effect of developing inhibitors. Gene therapy, on the other hand, can potentially prevent these limitations of current treatments. Although recombinant adeno-associated virus (rAAV) vectors are promising for deliver factor VIII gene, applying AAV vector technology to Hemophilia A gene therapy lagged behind other genetic diseases because of this size constraint (limited to ~5kb) and inefficient secretion of factor VIII protein. To improve factor VIII gene delivery utilizing rAAV vectors, we will develop a novel human factor VIII molecules with enhanced expression and secretion. The specific aims for this proposal are: 1). To develop a human factor VIII molecule with improved secretion and expression; 2). To develop a human factor VIII molecule with enhanced specific activity with minimal amino acid alteration; 3). To optimize the AAV factor VIII packaging and expression cassette and carry out preclinical studies in Hemophilia Animal Model. The success of this proposal may lead to a clinical trial of hemophilia A using AAV vectors.

 描述（由申请方提供）：人类人群中约有1/5000的男性患有凝血障碍，血友病A。这种疾病主要是由位于X染色体上的因子VIII基因缺陷引起的，并且难以通过常规药物治疗。目前通过静脉输注因子VIII浓缩物治疗血友病A非常昂贵，并且具有产生抑制剂的潜在副作用。另一方面，基因治疗可以潜在地防止当前治疗的这些局限性。尽管重组腺相关病毒（rAV）载体有望用于递送因子VIII基因，但由于大小限制（限制在~ 5 kb）和因子VIII蛋白分泌效率低下，将腺相关病毒载体技术应用于血友病A基因治疗落后于其他遗传性疾病。为了改善利用rAAV载体的因子VIII基因递送，我们将开发一种新的载体。 具有增强的表达和分泌的新的人因子VIII分子。这项建议的具体目标是：1）。开发具有改善的分泌和表达的人因子VIII分子; 2）.开发具有增强的比活性和最小的氨基酸改变的人因子VIII分子; 3）。目的优化重组腺相关病毒（AAV）因子VIII包装表达盒，并在血友病动物模型中进行临床前研究。这一提议的成功可能会导致使用AAV载体进行血友病A的临床试验。

项目成果

"D" matters in recombinant AAV DNA packaging.

“D”在重组 AAV DNA 包装中很重要。

• DOI: 10.1016/j.ymthe.2021.05.002
• 发表时间: 2021
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Zhang,Junping;Guo,Ping;Xu,Yinxia;Mulcrone,PatrickL;Samulski,RJude;Xiao,Weidong
• 通讯作者: Xiao,Weidong

Site-Specific N-Glycosylation on the AAV8 Capsid Protein.

• DOI: 10.3390/v10110644
• 发表时间: 2018-11-17
• 期刊: Viruses
• 作者: Aloor A;Zhang J;Gashash EA;Parameswaran A;Chrzanowski M;Ma C;Diao Y;Wang PG;Xiao W
• 通讯作者: Xiao W

Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment.

评估犬和人为因素VIII在基因递送中的生物学差异：人类血友病治疗的影响。

• DOI: 10.1038/gt.2016.34
• 发表时间: 2016-07
• 期刊: Gene therapy
• 影响因子: 5.1
• 作者: Wang Q;Dong B;Firrman J;Wu W;Roberts S;Moore AR;Liu LS;Chin MP;Diao Y;Kost J;Xiao W
• 通讯作者: Xiao W

Ultrasound-mediated gene delivery of factor VIII plasmids for hemophilia A gene therapy in mice.

• DOI: 10.1016/j.omtn.2022.01.006
• 发表时间: 2022-03-08
• 期刊: Molecular therapy. Nucleic acids
• 作者: Song S;Lyle MJ;Noble-Vranish ML;Min-Tran DM;Harrang J;Xiao W;Unger EC;Miao CH
• 通讯作者: Miao CH

Syngeneic AAV Pseudo-particles Potentiate Gene Transduction of AAV Vectors.

同基因 AAV 伪颗粒增强 AAV 载体的基因转导

• DOI: 10.1016/j.omtm.2016.12.004
• 发表时间: 2017-03-17
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Wang Q;Dong B;Pokiniewski KA;Firrman J;Wu Z;Chin MP;Chen X;Liu L;Xu R;Diao Y;Xiao W
• 通讯作者: Xiao W