Fuller David D, Rana Sabhya, Thakre Prajwal P, Benevides Ethan S, Pope Megan K, Todd Adrian G, Jensen Victoria N, Vaught Lauren, Cloutier Denise A, Ribas Roberto A, Larson Reece C, Gentry Matthew S, Sun Ramon C, Chandran Vijay, Corti Manuela, Falk Darin J, Byrne Barry J
Department of Physical Therapy, University of Florida, Gainesville, FL, USA; Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Department of Physical Therapy, University of Florida, Gainesville, FL, USA; Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Mol Ther. 2025 Sep 3;33(9):4276-4289. doi: 10.1016/j.ymthe.2025.06.022. Epub 2025 Jun 14.
Absence of functional acid-α-glucosidase (GAA) leads to early onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model (Gaa) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline) injection was done on postnatal day 1; rats were studied at 6-12 months old. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI) revealed that AAV-GAA treatment normalized diaphragm muscle glycogen as well as glycans. In vivo magnetic resonance imaging demonstrated that impaired cardiac volumes in Gaa rats were corrected by AAV-GAA treatment. Biochemical assays showed that AAV treatment increased GAA activity in the heart, diaphragm, quadriceps, and spinal cord. Inspiratory tidal volume and minute ventilation were increased in AAV-GAA-treated vs. saline-treated Pompe rats. Neurophysiological phrenic nerve recordings and spinal histological evaluation indicated that AAV-GAA treatment drove functional neuronal GAA expression. We conclude that neonatal AAV9-DES-GAA therapy drives sustained, functional GAA expression and improved cardiorespiratory function in the Gaa rat model of Pompe disease.
缺乏功能性酸性α-葡萄糖苷酶（GAA）会导致早发型庞贝病，并伴有心肺和神经肌肉功能衰竭。一种新型的庞贝大鼠模型（Gaa）被用于验证以下假设：用9型腺相关病毒（AAV9）进行新生儿基因治疗可在整个生命周期内恢复心肺神经肌肉功能。在出生后第1天经颞静脉给予AAV9-DES-GAA或进行假注射（生理盐水）；对6至12个月大的大鼠进行研究。基质辅助激光解吸/电离质谱成像（MALDI）显示，AAV-GAA治疗使膈肌糖原以及聚糖恢复正常。体内磁共振成像表明，AAV-GAA治疗纠正了Gaa大鼠受损的心脏容积。生化分析表明，AAV治疗增加了心脏、膈肌、股四头肌和脊髓中的GAA活性。与生理盐水治疗的庞贝大鼠相比，AAV-GAA治疗的大鼠吸气潮气量和分钟通气量增加。神经生理学膈神经记录和脊髓组织学评估表明，AAV-GAA治疗促使功能性神经元GAA表达。我们得出结论，在庞贝病的Gaa大鼠模型中，新生儿AAV9-DES-GAA治疗可促使GAA持续功能性表达并改善心肺功能。
