Development of a Topical Choroid Plexus Factor Product to Accelerate Wound Healin

开发局部脉络丛因子产品以加速伤口愈合

• 批准号: 8124285
• 负责人: Christopher Gordon Thanos
• 金额: $ 22.57万
• 依托单位: CYTOSOLV, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2012-12-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124285
• 关键词: Accounting; Admission activity; Adult; Adverse effects; Agreement; Amputation; Angiogenic Factor; Animal Sources; Animals; Antibiotics; Aquacel; Becaplermin; Biocompatible Materials; Biological; Biological Models; Biotechnology; Carboxymethylcellulose; Cerebrospinal Fluid; Chronic; Clinical; Clinical Research; Conditioned Culture Media; Corpus striatum structure; Coupled; Cutaneous; Data; Debridement; Dermal; Detection; Development; Devices; Diabetic Foot; Diabetic mouse; Diabetic ulcer; Disease; Dose; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Evaluation; Excitatory Neurotoxins; Exogenous Factors; Family suidae; Foundations; Freezing; Gel; Gene Expression Profile; Goals; Growth Factor; Hair follicle structure; Healed; Histologic; Hospitals; Hour; Human; Huntington Disease; Hydrogels; Immune; Immunohistochemistry; Impairment; In Vitro; Incidence; Individual; Industry; Infection Control; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Investigation; Kinetics; Letters; Liquid substance; Lower Extremity; Maintenance; Malignant Neoplasms; Measures; Methods; Modeling; Molecular Profiling; Mono-S; Mus; New Zealand; Non-Insulin-Dependent Diabetes Mellitus; Occlusive Dressings; Phase; Photography; Pilot Projects; Placebo Control; Platelet-Derived Growth Factor; Primates; Process; Proteins; Rattus; Recombinants; Reporting; Risk; Serum; Small Business Innovation Research Grant; Splint Device; Staging; Sterile coverings; Structure of choroid plexus; System; Technology; Therapeutic; Therapeutic Effect; Thick; Time; Tissues; Topical Antibiotic; Transforming Growth Factor beta; Translating; Vacuum; Vascular Endothelial Growth Factors; Weight; Weight-Bearing state; Work; Wound Healing; Xenograft procedure; angiogenesis; appendage; base; blood cerebrospinal fluid barrier; chemokine; clinical application; connective tissue growth factor; cytokine; db/db mouse; diabetic; healing; improved; mouse model; open wound; pre-clinical; regenerative; research and development; response; standard of care; success; therapeutic protein; treatment duration; virology; wound

DESCRIPTION (provided by applicant): Chronic superficial wounds are difficult to treat and often never completely heal. Diabetic foot complications account for the majority of lower limb amputations in the world, and 25% of all diabetic hospital admissions in the US. The standard of care for these wounds has been unchanged for decades, and remains reduced weight bearing, debridement, antibiotics, and dressings. Other therapies have been examined, including vacuum-assisted closure devices, biomaterial-based dressings, and growth factor therapies. Their impact has been marginal, with little clinical improvement over placebo controls, and often with increased risk of complications. Growth factor therapy, while promising, has not translated into dramatic clinical success with high doses of single exogenous factors. For example, Regranex topical gel (high dose recombinant platelet- derived growth factor), improves closure of diabetic ulcers but with an increased retrospective incidence of cancer. CytoSolv, Inc., has developed technology to simultaneously deliver multiple regenerative factors derived from cultured choroid plexus (CP) to accelerate wound healing at low therapeutic doses. These factors are present in the cerebrospinal fluid of normal adults, as the CP forms the blood- cerebrospinal fluid barrier and is involved in growth factor maintenance. Vascular endothelial growth factor, platelet derived growth factor, connective tissue growth factor, and transforming growth factor beta are among hundreds of potentially regenerative factors secreted by the CP. The synergy of the collective activities of CP factors allows CytoSolv's technology to potentially overcome the limitations and side effects of mono-factor therapy by delivering lower doses over reduced treatment duration. Pilot studies using lyophilized CP factors to treat wounds in normal rats revealed faster healing and vastly improved histological quality of healed tissue compared to topical antibiotic controls, including features such as hair follicles and other dermal appendages. These findings, coupled with the impressive portfolio of bioactive agents in the CP secretome, provide support for continued investigation. The potential clinical applications of an acellular CP product are numerous, but diabetic ulcers represent the greatest unmet need and our first target. The extent of ischemic disease in these individuals could be well served by the multiple biologic activities contained within the CP transcriptome. The proposal contained within this SBIR application seeks to (i) continue development of a topical product by incorporating factors secreted by the CP in culture supernatant into a non-occlusive dressing that provides at least 24 hours of continuous factor delivery, as determined in vitro; and (ii) assess the formulated product in open wounds created in the splinted db/db mouse model of Type I diabetes. These projects will provide fundamental data within a 6-month time frame that will allow the company to continue its goal developing a topical product to rebuild damage tissue in diabetic ulcers, and may also uncover additional information relevant to the pursuit of alternative disease indications. PUBLIC HEALTH RELEVANCE: The naturally occurring cocktail of bioactive molecules secreted by the choroid plexus is being developed by CytoSolv, Inc., as a topical regenerative product for accelerating superficial wound healing. The factors, which include many that are currently used in high dose mono-therapies to treat various forms of problematic wounds, range in biological activity from inflammation, to angiogenesis, to tissue rebuilding, and have demonstrated the ability to accelerate and improve the quality of wound repair in pilot studies in normal animals. CytoSolv aims to further characterize, formulate, and assess this early stage product in db/db diabetic mice, representing a stringent wound model with inherent healing impairments that mimic the company's target indication, diabetic ulcers.

描述(申请人提供)：慢性浅表伤口很难治疗，通常永远不会完全愈合。糖尿病足并发症占世界上大多数下肢截肢手术，占美国糖尿病住院患者总数的25%。这些伤口的护理标准几十年来一直没有改变，仍然减少了负重、清创、抗生素和敷料。其他疗法也被研究过，包括真空辅助闭合装置、生物材料敷料和生长因子疗法。它们的影响是微乎其微的，与安慰剂对照组相比，临床上几乎没有改善，而且往往会增加并发症的风险。生长因子疗法虽然前景看好，但在大剂量单一外源性因子治疗下并未转化为显著的临床成功。例如，Regranex外用凝胶(大剂量重组血小板衍生生长因子)可以改善糖尿病溃疡的愈合，但会增加癌症的回溯性发病率。CytoSolv，Inc.已经开发出一种技术，可以同时输送来自培养的脉络丛(CP)的多种再生素，以在低治疗剂量下加速伤口愈合。这些因子存在于正常成年人的脑脊液中，因为CP形成血-脑脊液屏障，并参与生长因子的维持。血管内皮生长因子、血小板衍生生长因子、结缔组织生长因子和转化生长因子β是CP分泌的数百种潜在的再生因子。CP因子的集体活动的协同作用使CytoSolv的技术有可能通过在缩短的治疗时间内提供更低的剂量来潜在地克服单因素疗法的限制和副作用。使用冻干CP因子治疗正常大鼠伤口的初步研究显示，与局部抗生素对照组相比，愈合组织的愈合速度更快，组织质量得到极大改善，包括毛囊和其他真皮附件等特征。这些发现，再加上CP分泌组中令人印象深刻的生物活性物质组合，为继续研究提供了支持。无细胞CP产品的潜在临床应用很多，但糖尿病溃疡是最大的未满足需求，也是我们的第一目标。CP转录组中包含的多种生物学活性可以很好地反映这些个体的缺血性疾病的程度。这项SBIR申请中包含的建议寻求(I)通过将培养上清液中CP分泌的因子加入到一种非闭塞敷料中来继续开发一种局部产品，该敷料可提供至少24小时的体外连续因子输送；以及(Ii)在I型糖尿病夹板db/db小鼠模型中评估配方产品。这些项目将在6个月的时间框架内提供基本数据，使该公司能够继续其目标，开发一种局部产品来重建糖尿病溃疡的受损组织，并可能发现与追求替代疾病适应症相关的更多信息。 与公共健康相关：由脉络丛分泌的天然生物活性分子鸡尾酒正在由CytoSolv公司开发，作为一种促进表面伤口愈合的局部再生产品。这些因子包括许多目前用于高剂量单一疗法治疗各种形式的问题伤口的因子，其生物活性范围从炎症到血管生成，再到组织重建，并在正常动物的初步研究中证明了加速和提高伤口修复质量的能力。CytoSolv的目标是在db/db糖尿病小鼠身上进一步表征、制定和评估这种早期产品，代表一种具有固有愈合损害的严格伤口模型，模拟该公司的目标适应症--糖尿病溃疡。