Lentiviral expressed growth factors as a novel therapy in wound healing

慢病毒表达生长因子作为伤口愈合的新疗法

• 批准号: 7481788
• 负责人: Boro Dropulic
• 金额: $ 11.91万
• 依托单位: LENTIGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481788
• 关键词: Acute; Adenovirus Vector; Adenoviruses; Adverse effects; Angiopoietin-1; Angiopoietin-2; Antiviral Agents; Apoptosis; Baltimore; Becaplermin; Biological Assay; Caring; Cell Proliferation; Cells; Chronic; Class; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Clonal Expansion; Closure; Collaborations; Communities; Consensus; Data; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic mouse; Diabetic ulcer; Diabetic wound; Diagnosis; Disease; Dose; Drug Formulations; Elderly; Electroporation; Embryo; Endopeptidases; Environment; Event; Exhibits; Facility Construction Funding Category; Fibroblasts; Fluorescence; Foot Ulcer; Funding; Future; Gel; Gene Delivery; Genes; Goals; Granulation Tissue; Growth Factor; Head; Healed; Histologic; Homeostasis; Human; Hypoxia; Immune response; In Vitro; Individual; Injury; Laboratories; Lead; Left; Leg Ulcer; Lentivirus Vector; Letters; Licensing; Measures; Mediating; Medicare; Mouse Cell Line; Mus; Mycoplasma; Numbers; Oxygen; Oxygen Consumption; Patients; Pennsylvania; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Placental Growth Factor; Platelet-Derived Growth Factor; Population; Preparation; Principal Investigator; Procedures; Process; Production; Property; Proteins; Proto-Oncogene Proteins c-sis; Protocols documentation; Public Health; Quality Control; Rate; Recombinants; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Site; Skin Ulcer; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Societies; Staging; Standards of Weights and Measures; Sterility; Technology; Testing; Therapeutic; Time; Tissues; Topical application; Transcription Coactivator; Transfection; Translating; United States Food and Drug Administration; Universities; Vascular Endothelial Growth Factors; Venous; Work; Wound Healing; angiogenesis; base; cellular transduction; chiron vaccine; cytokine; expression vector; gene gun; gene therapy; graft vs host disease; healing; hypoxia inducible factor 1; improved; in vivo; keratinocyte; killings; migration; mouse model; mutant; novel; novel strategies; plasmid DNA; platelet-derived growth factor BB; research clinical testing; research study; response; success; suicide gene; thymidylate kinase; transcription factor; transduction efficiency; vector; vector control; wound

DESCRIPTION (provided by applicant): Approximately 1 million people are diagnosed with venous leg ulcers annually in the U.S. and another 3 million worldwide. Currently, there are several approaches to wound healing treatment. Recombinant PDGF (Regranex, Ortho-McNeil) has been approved by the Food and Drug Administration (FDA) as a topically applied gel that acts biologically similarly to endogenous PDGF-BB by promoting chemotactic recruitment and proliferation of cells involved in wound repair. The consensus in the wound healing care community is that Regranex exhibited limited potential in clinical use. Despite its limited therapeutic success, Regranex is very expensive and is therefore beyond the means of elderly Medicare patients who represent the majority of the chronic wound population. Therefore, new therapies for wound healing are urgently needed. This proposal represents the revised project focused upon developing a novel gene therapy strategy for accelerated wound healing using Self Inactivating (SIN) lentiviral vectors (LV) that express hypoxia-inducible factor 1 (HIF-11), a transcription factor known to induce growth factors with wound healing properties. Treatment with HIF-11 expressed in LV might potentially serve as a much better therapy for wound healing than growth factors when applied directly to the wound. LVs are know to stably express genes with high efficiency, so it is hypothesized that stable expression of HIF-11 and HIF-11-induced growth factors at the wound site would lead to accelerated wound healing. In Aim 1 of this proposal we will develop SIN lentiviral vector that express HIF-11 as therapeutic payload, as well as control vector expressing green fluorescence protein (GFP). These vectors will also express the mutant human tmpk (TMPK) gene as an excellent safety feature. This suicide gene allows the transduced cells to be eliminated from the body once the wound healing process has been completed, thus limiting any potential complications because of prolonged expression of HIF-1 and growth factors induced by HIF-1 expression. Lentiviral vectors will be manufactured according to standard procedures and quality control will be performed prior to release for testing. In Aim 2 we will test the transduction efficiency of SIN.LV.HIF-11 and SIN.LV.GFP in vitro using mouse embryonic fibroblasts (MEFs). In Aim 3 we will test the ability of the LVs to prolong the expression of HIF-11-induced growth factors and to induce wound healing process at the wound site using diabetic mouse model. During Phase I Lentigen Corp. proposes studies that will ultimately generate proof of principle results, leading towards development of a novel, improved and safe gene therapy for the treatment of chronic wounds. Our new therapy is expected to be used in worldwide clinical settings for treatment of wound healing. PUBLIC HEALTH RELEVANCE This proposal focuses upon developing a novel gene therapy strategy for accelerated wound healing. There are 3.5 million patients with chronic skin ulcers in the U.S. alone (Wound Healing Society, 2003). The global figure is more than 14 million individuals. Two million people with diabetes will develop foot ulcers during their lifetimes. Currently, the only drug available for the treatment of diabetic foot ulcers is Regranex and it has a very limited success. Our new therapy will be affordable and is expected to be used in worldwide clinical settings for treatment of wound healing.

描述（由申请人提供）：美国每年约有100万人被诊断为静脉性腿部溃疡，全球另有300万人。目前，有几种治疗伤口愈合的方法。重组PDGF （Regranex, orthoo - mcneil）已获得美国食品和药物管理局（FDA）批准，作为一种局部应用凝胶，其生物学作用类似于内源性PDGF- bb，通过促进参与伤口修复的细胞的趋化募集和增殖。伤口愈合护理界的共识是瑞格尼克斯在临床应用中潜力有限。尽管它的治疗效果有限，但Regranex非常昂贵，因此超出了老年医疗保险患者的能力范围，他们代表了大多数慢性伤口患者。因此，迫切需要新的伤口愈合疗法。