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Autologous TGFB1 Modified CD34+ Stem Cells for Repair of Diabetic Macular Edema and Macular Ischemia

自体 TGFB1 修饰的 CD34 干细胞用于修复糖尿病黄斑水肿和黄斑缺血

基本信息

批准号：
9346796
负责人：
Stephen Hollis Bartelmez
金额：
$ 46.14万
依托单位：
BETASTEM THERAPUETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2019-01-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9346796
关键词：
Adult Adverse effects American Animal Model Australia Autologous Blindness Blood Blood Vessels Blood capillaries Bone Marrow CD34 gene CXCR4 gene Canada Cell Differentiation process Cell Proliferation Cells Chromosome Positioning Clinical Clinical Treatment Clinical Trials Development Diabetes Mellitus Diabetic Retinopathy Disease Disease Progression Dose Drug Kinetics Endothelium Europe Extravasation Eye Functional disorder Funding Generations Goals Healthcare Systems Heterochromatin Homing Human In Vitro Individual Injectable International Intravenous Investigational Drugs Ischemia Legal patent Lesion Measures Mission Mus Natural regeneration Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Ophthalmologist Oxygen PTPRC gene Papio Patients Perfusion Phase Quality of life Reperfusion Injury Research Research Personnel Retina Retinal Retinal Degeneration Safety Small Business Innovation Research Grant Stem cells Stromal Cell-Derived Factor 1 Subgroup Surface Antigens TGFB1 gene Therapeutic Time Toxicology Transforming Growth Factors Treatment Efficacy United States Food and Drug Administration United States National Institutes of Health Vascular Diseases Vascular Endothelium base capillary diabetic diabetic patient economic impact effective therapy experience experimental study immunosuppressed in vivo macula macular edema man meetings migration mouse model non-diabetic novel strategies patient safety peripheral blood phosphorodiamidate morpholino oligomer pre-clinical repaired response restoration retina blood vessel structure retinal damage retinal ischemia safety study safety testing stem cell population

项目摘要

Autologous TGFB1 Modified CD34+ Stem Cells for Repair of Diabetic Macular Edema and Macular Ischemia Retinal vascular diseases, such as diabetic macular edema and macular ischemia remain a common cause of vision loss and blindness. Diabetes can damage the small blood vessels in the retina causing them to leak and occlude resulting in vision loss. Although treatments are available for aspects of diabetic ocular disease no therapy is available to treat the damaged retinal vasculature and ischemic retina. Vision loss from retinal ischemia can be irreversible. A subgroup of DR patients suffers from macular ischemia and currently there is also no effective therapy. Research over the last decade has identified a class of bone marrow‐derived circulating cells, CD34+ stem cells, which are capable of homing to vascular lesions and facilitating vascular repair. However, many diabetic patients have dysfunctional CD34+ stem cells with no reparative potential. In this SBIR Fast Track phase l/ll proposal we use a novel strategy to correct dysfunctional diabetic CD34+ cells by transiently modifying CD34+ stem cells derived from patient blood that both restores perfusion to the ischemic retina and correct vessel leaking. Experiments from our NIH funded studies show that this CD34+ dysfunction can be corrected by transiently inhibiting endogenous transforming growth factor‐β 1 (TGF‐β1) within the patient's own dysfunctional CD34+ stem cells using antisense phosphorodiamidate morpholino oligomers (TGFβ1 PMO) to TGFβ1. Our proposed studies are focused according to guidance of the FDA. In 2012 we completed a pre‐IND meeting with the FDA. A major goal is to complete an IND in order to begin a first‐in‐man clinical trial. Our concern in developing this autologous stem cell approach is the safety of the patient and the efficacy of the therapy. We have proposed 5 in vitro phase l CD34+ studies and 5 phase ll in vivo studies (including Akimba mice and diabetic baboons), testing safety and efficacy of our therapy. The investigators of this application include a very experienced CEO, a well‐known practicing/research ophthalmologist, an international known PMO expert and a CD34+ stem cell biologist.

自体TGF β 1修饰的CD 34+干细胞对糖尿病黄斑水肿和缺血的修复作用视网膜血管疾病，如糖尿病性黄斑水肿和黄斑缺血仍然是视力的常见原因糖尿病会损害视网膜中的小血管，导致血管渗漏和阻塞。虽然糖尿病性眼部疾病的治疗方法是可行的，但没有治疗方法治疗受损的视网膜血管和缺血性视网膜。视网膜缺血导致的视力丧失可能是不可逆的。 DR患者的亚组患有黄斑缺血，目前也没有有效的治疗方法。在过去的十年中，已经确定了一类骨髓来源的循环细胞，CD 34+干细胞，能够归巢到血管病变并促进血管修复。然而，许多糖尿病患者在SBIR快速通道I/II期提案中，我们使用了一种新的通过瞬时修饰来自患者的CD 34+干细胞来纠正功能失调的糖尿病CD 34+细胞的策略血液既能恢复缺血视网膜的灌注，又能纠正血管渗漏。从我们 NIH 资助的研究表明，这种CD 34+功能障碍可以通过短暂抑制内源性转化来纠正，在患者自身功能失调的CD 34+干细胞内使用反义核酸检测生长因子-β 1（TGF-β1）磷酸二酰胺吗啉寡聚物（TGFβ1 PMO）转化为TGFβ1。 FDA的指导。2012年，我们与FDA完成了一次IND前会议。一个主要目标是在2012年完成IND。为了开始首次人体临床试验。我们在开发这种自体干细胞方法时关注的是安全性，我们已经提出了5项体外I期CD 34+研究和5项II期研究，体内研究（包括Akimba小鼠和糖尿病狒狒），测试我们疗法的安全性和有效性。本申请的研究者包括一位非常有经验的CEO，一位著名的执业/研究眼科医生，国际知名PMO专家和CD 34+干细胞生物学家。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isolation and analysis of primitive hemopoietic progenitor cells on the basis of differential expression of Qa-m7 antigen.

基于Qa-m7抗原差异表达的原始造血祖细胞的分离和分析。

DOI：
发表时间：
1986
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Bertoncello,I;Bartelmez,SH;Bradley,TR;Stanley,ER;Harris,RA;Sandrin,MS;Kriegler,AB;McNiece,IK;Hunter,SD;Hodgson,GS
通讯作者：
Hodgson,GS

Interleukin 1 plus interleukin 3 plus colony-stimulating factor 1 are essential for clonal proliferation of primitive myeloid bone marrow cells.

白细胞介素 1 加白细胞介素 3 加集落刺激因子 1 对于原始骨髓细胞的克隆增殖至关重要。

DOI：
发表时间：
1989
期刊：
Experimental hematology
影响因子：
2.6
作者：
Bartelmez,SH;Bradley,TR;Bertoncello,I;Mochizuki,DY;Tushinski,RJ;Stanley,ER;Hapel,AJ;Young,IG;Kriegler,AB;Hodgson,GS
通讯作者：
Hodgson,GS

Investigator profile.

研究者简介。