Gene Based Therapy for Congestive Heart Failure

描述（由申请人提供）：充血性心力衰竭是美国发病率和死亡率的主要原因。虽然常规治疗的进展在降低心力衰竭死亡率方面取得了稳定和渐进的进展，但迫切需要探索新的治疗方法。基因治疗最初应用于遗传性单基因疾病的临床环境。现在很明显，基因疗法在充血性心力衰竭等疾病中具有更广泛的潜力。随着我们对心力衰竭分子机制的理解的提高，沿着新的和更安全的基因递送载体的开发，已经鉴定出难以操作但可能更适合基因治疗的新靶点。在过去的几年里，钙循环异常，特别是肌浆网钙摄取不足已成为晚期心力衰竭的标志。SERCA 2a-受磷蛋白-蛋白磷酸酶1的复合物一直难以靶向腺苷。然而，来自CUPID试验的令人鼓舞的结果，其中AAV1.SERCA2a基因转移被发现是安全的，并且在2期研究中证明了临床结果、症状、功能状态、NT-proBNP和心脏结构的益处，再次验证了钙循环是心力衰竭治疗的重要靶点。因此，I-1c及其额外的益处正在成为治疗心力衰竭的重要和有效的靶点。尽管AAV载体已在包括CUPID试验的许多试验中显示是安全的，但当用于心力衰竭的情况时，它们具有以下限制：1）它们对心脏不是特异性的，并且2预先存在的针对任何单个血清型的中和抗体将导致排除一种或多种抗体。 大部分患者。事实上，在CUPID试验中，50%的筛选的心力衰竭患者不得不被排除，因为他们具有针对AAV 1的中和抗体滴度。Nanocor Inc.已经开发了一种嵌合的AAV，更具体地针对心脏和逃避患者的固有免疫力。我们已经提出使用这些新的嵌合载体，也被称为生物纳米颗粒（BNP），直接靶向I-1在心力衰竭的实验模型。在本I期申请中，我们将在心力衰竭临床前模型中进行BNP116.CMV.I1c通过冠状动脉内输注的剂量递增疗效研究。! 公共卫生相关性：虽然心力衰竭的常规治疗进展正在稳步和渐进地降低心力衰竭死亡率，但迫切需要探索新的治疗方法。现在很明显，基因治疗是治疗充血性心力衰竭的一个可行的选择。为此，Nanocor开发了一种靶向心肌细胞中抑制剂1蛋白的AAV载体的心脏嵌合体，它将在第1阶段SBIR资助中进行测试。

DESCRIPTION (provided by applicant): Congestive heart failure is a major cause of morbidity and mortality in the United States. While progress in conventional treatments is making steady and incremental gains to reduce heart failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy was initially applied in the clinical setting for inherited monogenic disorders. It is now apparent that gene therapy has broader potential in diseases such as congestive heart failure. Improvement in our understanding of the molecular mechanisms of heart failure, along with the development of novel and safer vectors for gene delivery, have led to the identification of novel targets that are difficult to manipulate pharmacologically but may be more amenable to gene therapy. In the last few years calcium cycling abnormalities and specifically deficiencies in sarcoplasmic reticulum calcium uptake have been hallmarks of advanced heart failure. The complex of SERCA2a-phospholamban-Protein phospatase 1 has been difficult to target pharmacologically. However the encouraging results from the CUPID trial in which AAV1.SERCA2a gene transfer was found to be safe and demonstrated benefit in clinical outcomes, symptoms, functional status, NT-proBNP and cardiac structure in a phase 2 study, has once again validated calcium cycling as being an important target for heart failure treatment. For this reason, I-1c with its additional benefits is emerging s an important and valid target for the treatment of heart failure. Even though AAV vectors have been shown to be safe in a number of trials including the CUPID trial, they have the following limitations when used in the setting of heart failure: 1) they are not specific for the heart and 2 pre-existence neutralizing antibodies to any individual serotype would result in the exclusion of a large percentage of the patients. In fact in the CUPID trial 50% of the screened heart failure patients had to be excluded because they had neutralizing antibody titers against AAV1. Nanocor Inc. has developed a chimeric of AAV that more specifically targets the heart and escapes the inherent immunity in patients. We have proposed to use of these novel chimeric vectors, which are also known as Bio Nano Particles (BNP), to directly target I-1 in experimental models of heart failure. In this phase 1 application, we will carry out a dose-escalation efficacy study of BNP116.CMV.I1c by Intra-Coronary Infusion in a pre-clinical model of heart failure. ! PUBLIC HEALTH RELEVANCE: While progress in conventional treatments for heart failure is making steady and incremental gains to reduce heart failure mortality, there is a critical need to explore new therapeutic approaches. It is now apparent that gene therapy is a viable option for the treatment of congestive heart failure. To this end, Nanocor has developed a cardiotropic chimeric of AAV vector targeting the inhibitor 1 protein in cardiomyocytes which it will test in ths phase 1 SBIR grant.