Carpenter Marco D, Kus Nicole, Choi Rosa B, Said Hooda, Dumitru Ana Maria, Bauer Jackson H, Wang Samantha, Luks Valerie, Teerdhala Sriya, Shah Aarsha, Zoltick Philip W, Alameh Mohamad G, Peranteau William
Division of General, Thoracic, and Fetal Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
The Center for Fetal Research at The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Mol Ther Methods Clin Dev. 2025 Sep 26;33(4):101599. doi: 10.1016/j.omtm.2025.101599. eCollection 2025 Dec 11.
Base editing provides a unique opportunity for the permanent correction of central nervous system (CNS) diseases with early onset pathology. While lipid nanoparticles (LNPs) have emerged as an effective messenger RNA (mRNA) delivery system for liver base editing, extrahepatic delivery of base editing components to the CNS is poor. To identify CNS-penetrant LNPs, we profiled cell-type-specific mRNA-LNP delivery across developmental stages in the liver and CNS. We identified one LNP (LNP1) with efficient mRNA delivery to endothelial cells, microglia, and neurons in the cortex of fetal recipients. We then applied these findings to spinal muscular atrophy (SMA) and systemically delivered LNP1, encapsulating adenine base editor mRNA and a therapeutic single guide RNA (gRNA) for the upregulation of survival of motor neuron 2 (SMN2) in a humanized severe mouse model of SMA. We demonstrated base editing in the liver and the cortex. Despite low levels of editing in CNS organs, fetal administration modestly increased survival in SMA mice, providing a foundation for a fetal base editing approach for SMA. In conclusion, we leverage our discovery related to basic fetal biology and its influences on mRNA-LNP delivery to develop clinically relevant CNS therapies.
碱基编辑为永久性纠正具有早期发病病理的中枢神经系统（CNS）疾病提供了独特的机会。虽然脂质纳米颗粒（LNPs）已成为用于肝脏碱基编辑的有效信使核糖核酸（mRNA）递送系统，但碱基编辑组件向中枢神经系统的肝外递送效果不佳。为了鉴定可穿透中枢神经系统的LNPs，我们分析了肝脏和中枢神经系统发育阶段的细胞类型特异性mRNA-LNP递送情况。我们鉴定出一种LNP（LNP1），它能有效地将mRNA递送至胎儿受体皮质中的内皮细胞、小胶质细胞和神经元。然后，我们将这些发现应用于脊髓性肌萎缩症（SMA），并在人源化严重SMA小鼠模型中全身递送包裹腺嘌呤碱基编辑器mRNA和治疗性单向导RNA（gRNA）的LNP1，以上调运动神经元2（SMN2）的存活率。我们在肝脏和皮质中证实了碱基编辑。尽管中枢神经系统器官中的编辑水平较低，但胎儿期给药适度提高了SMA小鼠的存活率，为SMA的胎儿碱基编辑方法奠定了基础。总之，我们利用与胎儿基础生物学及其对mRNA-LNP递送的影响相关的发现来开发临床相关的中枢神经系统疗法。
