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。虽然传统治疗方法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治疗。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，以及新型和更安全的基因传递载体的发展，已经导致鉴定出难以从药理学上操纵但可能更适合基因治疗的新靶点。在过去的几年中，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。serca2 -磷酸蛋白磷酸酶1复合体在药理学上很难定位。然而，令人鼓舞的结果，从丘比特试验中，AAV1。SERCA2a基因转移是安全的，在临床结果、症状、功能状态、NT-proBNP和心脏结构方面均有益处，再次验证了钙循环是心力衰竭治疗的重要靶点。因此，具有额外益处的I-1c正成为治疗心力衰竭的重要而有效的靶点。尽管AAV载体在包括CUPID试验在内的许多试验中已被证明是安全的，但在心力衰竭的情况下，它们有以下局限性：1)它们不是针对心脏的特异性抗体；2)预先存在的针对任何个体血清型的中和抗体将导致排除a

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.