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

描述（由申请人提供）：慢性浅表伤口难以治疗，通常无法完全愈合。糖尿病足并发症占世界上下肢截肢的大多数，占美国所有糖尿病住院的25%。这些伤口的护理标准几十年来一直没有改变，仍然是减轻负重、清创、抗生素和敷料。其他治疗方法也在研究中，包括真空辅助闭合装置、生物材料敷料和生长因子疗法。它们的影响是微不足道的，与安慰剂对照相比几乎没有临床改善，并且经常增加并发症的风险。生长因子治疗，虽然有前途，并没有转化为戏剧性的临床成功与高剂量的单一外源性因子。例如，Regranex局部凝胶（高剂量重组血小板衍生生长因子）改善了糖尿病溃疡的闭合，但增加了癌症的回顾性发病率。CytoSolv，Inc.，已经开发出同时递送来自培养的脉络丛（CP）的多种再生因子的技术，以在低治疗剂量下加速伤口愈合。这些因子存在于正常成人的脑脊液中，因为CP形成血-脑脊液屏障并参与生长因子维持。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分泌的数百种潜在再生因子中的一种。CP因子的集体活性的协同作用使CytoSolv的技术能够通过在缩短的治疗时间内提供较低的剂量来克服单因子治疗的局限性和副作用。使用冻干CP因子治疗正常大鼠伤口的初步研究显示，与局部抗生素对照相比，愈合组织的愈合速度更快，组织学质量大大改善，包括毛囊和其他皮肤附件等特征。这些发现，再加上令人印象深刻的组合的生物活性剂在CP分泌，为继续调查提供了支持。脱细胞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，也是我们的首要目标。这些个体中缺血性疾病的程度可以通过CP转录组中包含的多种生物活性来很好地服务。该SBIR申请中包含的建议旨在（i）通过将培养上清液中CP分泌的因子掺入非封闭性敷料中继续开发局部产品，该敷料提供至少24小时的连续因子递送，如体外测定的;和（ii）评估I型糖尿病夹板db/db小鼠模型中产生的开放性伤口中的配制产品。这些项目将在6个月的时间内提供基本数据，使公司能够继续开发局部产品以重建糖尿病溃疡中的受损组织，并可能发现与寻求替代疾病适应症相关的其他信息。 公共卫生相关性：由脉络丛分泌的生物活性分子的天然混合物正在由CytoSolv公司开发，作为加速浅表伤口愈合的局部再生产品。这些因子包括目前用于高剂量单一疗法以治疗各种形式的有问题伤口的许多因子，其生物活性范围从炎症到血管生成到组织重建，并且已经在正常动物的初步研究中证明了加速和改善伤口修复质量的能力。CytoSolv旨在db/db糖尿病小鼠中进一步表征、配制和评估这种早期产品，代表具有固有愈合障碍的严格伤口模型，模拟公司的目标适应症糖尿病溃疡。

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.