AAV-mediated delivery of eCD4-Ig for prevention and treatment of perinatal HIV infection

AAV 介导的 eCD4-Ig 递送用于预防和治疗围产期 HIV 感染

• 批准号: 10644033
• 负责人: Mauricio de Aguiar Martins
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644033
• 关键词: AAV; mediated; delivery; eCD4; Ig

PROJECT SUMMARY Mother-to-child transmission of human immunodeficiency virus (HIV) still results in hundreds of thousands of new pediatric HIV infections every year, especially in resource-poor areas of the world where access to antenatal/postnatal antiretroviral therapy (ART) is limited. Sadly, in the absence of ART, >50% of HIV- infected infants die by 2 years of age. Since ART alone will not be sufficient to end the morbidity and mortality associated with HIV/AIDS in children, there is an urgent need for developing practical interventions to prevent and treat pediatric HIV infection. To that end, this project will evaluate the potential of gene therapy with the potent and extremely broad HIV inhibitor eCD4-Ig to prevent and treat perinatal HIV infection. eCD4-Ig is a chimeric molecule consisting of the outer domains of CD4, an IgG Fc portion, and a co-receptor mimetic peptide. eCD4-Ig has unmatched breadth and very potent effector activities against HIV-1, HIV-2, and SIV. The eCD4-Ig gene will be delivered to infant rhesus macaques (RMs) via adeno-associated virus (AAV)-mediated gene transfer. AAV vectors are safe and can transduce both dividing and non-dividing cells. Critically, AAV-driven transgene expression in long-lived cells, such as those of skeletal muscle, can last for years, possibly decades. While AAV-mediated delivery of eCD4-Ig has been shown to protect adult RMs against challenge with pathogenic immunodeficiency viruses bearing highly divergent envelope proteins, this approach has never been tested in infants. We have recently partnered with the Farzan lab to characterize the kinetics of eCD4-Ig expression in infant RMs treated with AAV/eCD4-Ig at birth. Compared to adult animals, AAV/eCD4-Ig-treated newborn RMs experienced substantially higher levels of eCD4-Ig and lower levels of antibodies against the eCD4-Ig molecule. Note that these anti-drug antibodies (ADAs) are highly detrimental to AAV-mediated delivery of immunoglobulins because they can clear the molecules from circulation, thereby reducing the efficacy of this approach. The low levels of ADAs observed in the AAV/eCD4-Ig-treated infants is consistent with previous reports of neonates developing tolerance to AAV-delivered transgene products. Given the ability of AAV vectors to promote sustained transgene expression after a one-time administration, and the unique window of opportunity offered by the neonatal period to achieve robust AAV-driven expression of eCD4-Ig in vivo, we postulate that AAV-mediated delivery of eCD4-Ig to infants can prevent and treat postpartum HIV infection. In specific aim (SA) 1, we will characterize the safety profile of AAV/eCD4-Ig in infant RMs. In SA 2, we will determine if neonatal delivery of AAV/eCD4-Ig can prevent oral acquisition of SIVmac239 in RMs. In SA 3, we will assess if AAV-mediated delivery of eCD4-Ig to SIV-infected infant RMs can control viral replication without ART. If successful, the proposed experiments will build the pre-clinical foundation for testing AAV-mediated gene therapy with eCD4-Ig in infants as a means to prevent and treat perinatal HIV infection.

项目摘要 人类免疫缺陷病毒（HIV）的母子传播仍会导致数百种 每年成千上万的新儿科艾滋病毒感染，尤其是在世界上贫乏的地区 获得产后/产后抗逆转录病毒疗法（ART）的机会是有限的。可悲的是，在没有艺术的情况下，> 50％的HIV- 感染婴儿死亡2岁。因为仅艺术就不足以终止发病率和死亡率 与儿童的艾滋病毒/艾滋病有关，迫切需要制定实际干预措施以防止 并治疗小儿艾滋病毒感染。为此，该项目将评估基因治疗的潜力 有效且极宽的HIV抑制剂ECD4-Ig可预防和治疗围产期HIV感染。 ECD4-ig是一个 嵌合分子由CD4的外域，IgG FC部分和共受体模拟肽组成。 ECD4-Ig具有针对HIV-1，HIV-2和SIV的无与伦比的广度和非常有效的效应活动。 ECD4-Ig 基因将通过腺相关病毒（AAV）介导的基因传递给婴儿恒河猕猴（RMS） 转移。 AAV矢量是安全的，可以散发分裂和非分裂细胞。至关重要的是，AAV驱动 长寿命细胞中的转基因表达（例如骨骼肌的细胞）可能持续数年，甚至可以持续数十年。 虽然已显示AAV介导的ECD4-Ig的递送可保护成人RMS免受致病性的挑战 具有高度不同包膜蛋白的免疫缺陷病毒，这种方法从未在 婴儿。我们最近与Farzan Lab合作，表征了ECD4-Ig表达的动力学 出生时用AAV/ECD4-Ig处理的婴儿RMS。与成年动物相比，AAV/ECD4-IG处理的新生儿RMS 具有较高水平的ECD4-Ig和针对ECD4-Ig分子的抗体水平较低。 请注意，这些抗药物抗体（ADA）对AAV介导的免疫球蛋白的递送高度有害 因为他们可以从循环中清除分子，从而降低了这种方法的功效。低 在AAV/ECD4-IG治疗的婴儿中观察到的ADA水平与以前的新生儿报道一致 开发对AAV传递的转基因产品的耐受性。鉴于AAV向量促进持续的能力 一次性管理后的转基因表达，以及独特的机会窗口 新生儿时期实现了体内Ecd4-ig的稳健AAV驱动的表达，我们假设AAV介导 将ECD4-Ig递送给婴儿可以预防和治疗产后HIV感染。在特定目标（SA）1中，我们将 表征婴儿RMS中AAV/ECD4-Ig的安全性。在SA 2中，我们将确定新生儿的传递是否 AAV/ECD4-Ig可以防止在RMS中口服SIVMAC239。在SA 3中，我们将评估AAV介导的 将ECD4-Ig传递到SIV感染的婴儿RMS可以控制病毒复制而无需艺术。如果成功， 拟议的实验将建立临床前基础，用于测试用ECD4-Ig测试AAV介导的基因治疗 在婴儿中，作为预防和治疗围产期HIV感染的一种手段。