Translational Studies of Paracrine CV Gene Transfer
旁分泌 CV 基因转移的转化研究
基本信息
- 批准号:8328595
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:ApoptoticAwardBiodistributionBlood CirculationCCI-779CardiacCardiovascular DiseasesCardiovascular systemClinical TrialsCongestive Heart FailureDependovirusDiseaseDistantDoseDoxycyclineFamily suidaeFundingGene TransferGoalsHeartHeart DiseasesHeart failureHormonesImmune responseInjection of therapeutic agentInsulin-Like Growth Factor IIntramuscular InjectionsIntravenousLaboratoriesLength of StayMediatingMethodsModelingMorbidity - disease rateMyocardiumOffice VisitsPatientsPeptidesPopulationPrimatesRattusRegulationResearch DesignRodentSafetySerotypingSerumSiteSkeletal MuscleSystemTestingTetracyclinesTherapeuticToxic effectTransgenesVeteransVirusWater Supplyadeno-associated viral vectorbaseeconomic costimproved functioningintravenous injectionnovelparacrinepromoterresponseselective expressiontherapeutic transgenetransgene expressiontranslational studyvector
项目摘要
DESCRIPTION (provided by applicant):
Gene transfer for the treatment of cardiovascular diseases is conceptually attractive, but difficulty in obtaining high yield transgene expression in the heart in a manner that can be easily and safely applied has been a chief impediment to progress. Current methods of gene transfer for heart disease include intramuscularinjection into heart muscle or intracoronary delivery, approaches that typically provide limited expression or are cumbersome to apply. Consequently, we have considered the usefulness of a vector encoding a paracrine-type transgene. In this approach, the transgene acts as a hormone, having cardiac effects after being released to the circulation from a distant site. This approach would circumvent the problem of attaining high yield cardiac gene transfer and enable patients to be treated by a systemic injection during an office visit. Furthermore, the approach proposed would eliminate the need for intravenous delivery of therapeutic peptides and thereby circumvent repeated and prolonged hospital stays, high morbidity, and enormous economic costs. The most suited vector to achieve these goals is the adeno-associated virus (AAV), which provides long term and extensive expression after intravenous delivery in rodents, pigs, and primates. Finally, by using regulated expression of the transgene in the AAV vector, one can achieve control of the level of transgene expression. To develop and optimally refine this approach is the focus of this proposal. Insulin-like growth factor-I (IGFI) is a peptide with protean favorable cardiovascular effects (inotrope, angiogenic, anti-apoptotic). Proof-of-concept studies in our laboratory recently showed that skeletal muscle injection of an AAV5 vector encoding IGFI improved function of the failing rat heart. IGFI will be an ideal therapeutic transgene in the proposed studies. To develop and refine such an approach, we propose to determine: a) mechanisms by which IGFI gene transfer increases contractile function; b) the optimal AAV vector and promoter for intravenous delivery that will provide maximal transgene expression with minimal immune response and off-target effects in rats; c) the optimal regulated transgene expression system to enable fine-tuning of serum transgene levels, and turning expression off and on as needed; d) the safety, efficacy, and survival advantage of IGFI gene transfer, using this optimal, paracrine-based approach in a rat model of congestive heart failure; and e) e) the minimally effective doses of AAV and activators of transgene expression following intravenous delivery of this optimal vector in normal pigs, using serum IGFI and immune response as end-points. These mechanistic and proof-of-concept studies are designed to be sufficient in scope to launch, under separate funding, a study in pigs with CHF, and subsequently to file an IND application to the FDA for the penultimate study: a clinical trial in veterans with congestive heart failure.
描述(由申请人提供):
用于治疗心血管疾病的基因转移在概念上是有吸引力的,但是在以一种可以轻松,可以安全地应用的方式获得高产转基因表达的困难是进步的主要障碍。心脏病的基因转移方法的当前方法包括肌内注射对心脏肌肉或冠状内递送,通常提供有限的表达或繁琐的应用。因此,我们考虑了编码旁分泌型转基因的向量的有用性。在这种方法中,转基因充当激素,从远处释放到循环后具有心脏影响。这种方法将避免获得高产量心脏基因转移的问题,并使患者在办公室访问期间接受全身注射治疗。此外,提出的方法将消除对治疗性肽静脉输送的需求,从而规避重复和延长住院,高发病率和巨大的经济成本。实现这些目标的最合适的载体是与腺相关的病毒(AAV),该病毒在啮齿动物,猪和灵长类动物的静脉内递送后提供了长期和广泛的表达。最后,通过使用AAV载体中的转基因的调节表达,可以控制转基因表达水平。开发并最佳地完善这种方法是该提案的重点。 胰岛素样生长因子-I(IGFI)是一种具有蛋白质有利心血管作用(肌肉,血管生成,抗凋亡)的肽。我们实验室中的概念验证研究最近表明,编码IGFI改善大鼠心脏功能的AAV5载体的骨骼肌注射。在拟议的研究中,IGFI将是理想的治疗转基因。 为了开发和完善这种方法,我们建议确定:a)IGFI基因转移增加收缩功能的机制; b)静脉输送的最佳AAV载体和启动子,将提供最大的转基因表达,而大鼠的免疫反应最小和靶向效果最小; c)最佳调节的转基因表达系统,以实现血清转基因水平的微调,并根据需要关闭表达; d)使用这种最佳的,基于旁分泌的方法,在充血性心力衰竭的大鼠模型中,使用这种最佳的,基于旁分泌的方法的安全性,功效和生存优势; e)e)使用血清IGFI和免疫反应作为终点,在正常猪中静脉注射该最佳载体后,该最佳载体静脉输送后,AAV的最低有效剂量和转基因表达的激活剂。这些机械和概念验证研究的设计旨在足以发射,在单独的资金下,对具有CHF的猪进行研究,随后向FDA提出IND申请倒数第二次研究:一项充满充血性心力衰竭的退伍军人的临床试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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H. Kirk Hammond其他文献
H. Kirk Hammond的其他文献
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