MacLachlan Timothy K, Milton Mark N, Turner Oliver, Tukov Francis, Choi Vivian W, Penraat Jan, Delmotte Marie-Hélène, Michaut Lydia, Jaffee Bruce D, Bigelow Chad E
Preclinical Safety, Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Mol Ther Methods Clin Dev. 2017 Dec 22;8:105-120. doi: 10.1016/j.omtm.2017.12.001. eCollection 2018 Mar 16.
Retinitis pigmentosa is a form of retinal degeneration usually caused by genetic mutations affecting key functional proteins. We have previously demonstrated efficacy in a mouse model of deficiency with a self-complementary AAV8 vector carrying the gene for human under control of a short promoter (CPK850). In this article, we describe the nonclinical safety profile of this construct as well as updated efficacy data in the intended clinical formulation. In mice dosed at a range of CPK850 levels, a minimum efficacious dose of 3 × 10 vg in a volume of 1 μL was observed. For safety assessment in these and mice, optical coherence tomography (OCT) and histopathological analysis indicated retinal thinning that appeared to be dose-dependent for both genotypes, with no qualitative difference noted between and mice. In a non-human primate study, mRNA expression was detected and dose dependent intraocular inflammation and retinal thinning were observed. Inflammation resolved slowly over time and did not appear to be exacerbated in the presence of anti-AAV8 antibodies. Biodistribution was evaluated in rats and satellite animals in the non-human primate study. The vector was largely detected in ocular tissues and low levels in the optic nerve, superior colliculus, and lateral geniculate nucleus, with limited distribution outside of these tissues. These data suggest that an initial subretinal dose of ∼3 × 10 vg/μL CPK850 can safely be used in clinical trials.
视网膜色素变性是一种视网膜退化形式，通常由影响关键功能蛋白的基因突变引起。我们之前已经在一个缺乏症小鼠模型中证明了携带人基因的自我互补腺相关病毒8载体（CPK850）在短启动子（CPK850）控制下的有效性。在本文中，我们描述了该构建体的非临床安全性概况以及预期临床制剂中的最新疗效数据。在以一系列CPK850水平给药的小鼠中，观察到在1 μL体积中最低有效剂量为3×10 vg。为了对这些小鼠和其他小鼠进行安全性评估，光学相干断层扫描（OCT）和组织病理学分析表明视网膜变薄，这在两种基因型中似乎都是剂量依赖性的，在两种小鼠之间未观察到定性差异。在一项非人灵长类动物研究中，检测到了mRNA表达，并观察到剂量依赖性的眼内炎症和视网膜变薄。炎症随着时间的推移缓慢消退，并且在存在抗AAV8抗体的情况下似乎没有加剧。在大鼠和非人灵长类动物研究中的卫星动物中评估了生物分布。该载体主要在眼组织中检测到，在视神经、上丘和外侧膝状体中含量较低，在这些组织之外的分布有限。这些数据表明，约3×10 vg/μL CPK850的初始视网膜下剂量可安全用于临床试验。
