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Aerosol Delivery of Synthetic mRNA to Vaginal Mucosa Leads to Durable Expression of Broadly Neutralizing Antibodies against HIV.
Molecular Therapy ( IF 12.4 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.ymthe.2020.01.002
Kevin E Lindsay 1 , Daryll Vanover 1 , Merrilee Thoresen 2 , Heath King 2 , Peng Xiao 3 , Peres Badial 2 , Mariluz Araínga 3 , Seong Bin Park 4 , Pooja M Tiwari 1 , Hannah E Peck 1 , Emmeline L Blanchard 1 , Jean M Feugang 4 , Alicia K Olivier 2 , Chiara Zurla 1 , Francois Villinger 3 , Amelia R Woolums 2 , Philip J Santangelo 1
Affiliation  

There is a clear need for low-cost, self-applied, long-lasting approaches to prevent human immunodeficiency virus (HIV) infection in both men and women, even with the advent of pre-exposure prophylaxis (PrEP). Broadly neutralizing antibodies represent an option to improve HIV prophylaxis, but intravenous delivery, cold-chain stability requirements, low cervicovaginal concentrations, and cost may preclude their use. Here, we present an approach to express the anti-GP120 broadly neutralizing antibody PGT121 in the primary site of inoculation, the female reproductive tract, using synthetic mRNA. Expression is achieved through aerosol delivery of unformulated mRNA in water. We demonstrated high levels of antibody expression for over 28 days with a single mRNA administration in the reproductive tract of sheep. In rhesus macaques, neutralizing antibody titers in secretions developed within 4 h and simian-HIV (SHIV) infection of ex vivo explants was prevented. Persistence of PGT121 in vaginal secretions and epithelium was achieved through the incorporation of a glycosylphosphatidylinositol (GPI) anchor into the heavy chain of the antibody. Overall, we present a new paradigm to deliver neutralizing antibodies to the female reproductive tract for the prevention of HIV infections.

中文翻译:

将合成 mRNA 气溶胶递送至阴道粘膜可导致抗 HIV 广泛中和抗体的持久表达。

即使暴露前预防 (PrEP) 出现,仍然明显需要低成本、自我应用、持久的方法来预防男性和女性人类免疫缺陷病毒 (HIV) 感染。广泛中和抗体代表了改善 HIV 预防的一种选择,但静脉注射、冷链稳定性要求、低宫颈阴道浓度和成本可能妨碍其使用。在这里,我们提出了一种使用合成 mRNA 在主要接种部位(女性生殖道)中表达抗 GP120 广泛中和抗体 PGT121 的方法。通过将未配制的 mRNA 在水中气雾输送来实现表达。我们在绵羊生殖道中施用单次 mRNA 后,证明了抗体的高水平表达超过 28 天。在恒河猴中,4 小时内分泌物中出现中和抗体滴度,并且预防了离体外植体的猿猴 HIV (SHIV) 感染。通过将糖基磷脂酰肌醇 (GPI) 锚结合到抗体的重链中,实现了 PGT121 在阴道分泌物和上皮细胞中的持久存在。总的来说,我们提出了一种向女性生殖道提供中和抗体以预防艾滋病毒感染的新范例。
更新日期:2020-01-11
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