Fernandes-Pires Gabriella, Azevedo Marcelo Duarte, Lanzillo Marc, Roux-Petronelli Clothilde, Binz Pierre-Alain, Cudalbu Cristina, Sandi Carmen, Tenenbaum Liliane, Braissant Olivier
Service of Clinical Chemistry, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland.
Laboratory of Cellular and Molecular Neurotherapies, Clinical Neurosciences Department, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland.
Mol Ther Methods Clin Dev. 2024 Apr 23;32(2):101251. doi: 10.1016/j.omtm.2024.101251. eCollection 2024 Jun 13.
Creatine deficiency syndromes (CDS), caused by mutations in (AGAT), , and , mainly affect the central nervous system (CNS). CDS show brain creatine (Cr) deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy, and motor dysfunction. AGAT/GAMT-deficient patients lack brain Cr synthesis but express the Cr transporter SLC6A8 at the blood-brain barrier and are thus treatable by oral supplementation of Cr. In contrast, no satisfactory treatment has been identified for Cr transporter deficiency (CTD), the most frequent of CDS. We used our CTD rat model to develop a new -driven gene therapy re-establishing the functional Slc6a8 transporter in rat CNS. We show, after intra-cisterna magna vector injection of postnatal day 11 pups, the transduction of Slc6a8-FLAG in cerebellum, medulla oblongata, and spinal cord as well as a partial recovery of Cr in these brain regions, together with full prevention of locomotion defaults and impairment of myocyte development observed in male rats. While more work is needed to correct those CTD phenotypes more associated with forebrain structures, this study is the first demonstrating positive effects of an -driven gene therapy on CTD and thus represents a very encouraging approach to treat the so-far untreatable CTD.
肌酸缺乏综合征（CDS）由精氨酸甘氨酸脒基转移酶（AGAT）、胍基乙酸甲基转移酶（GAMT）和SLC6A8基因突变引起，主要影响中枢神经系统（CNS）。CDS表现为脑肌酸（Cr）缺乏、伴有严重语言发育迟缓的智力障碍、行为问题、癫痫和运动功能障碍。AGAT/GAMT缺乏的患者缺乏脑Cr合成，但在血脑屏障处表达Cr转运体SLC6A8，因此可通过口服补充Cr进行治疗。相比之下，对于最常见的CDS类型——Cr转运体缺乏症（CTD），尚未确定令人满意的治疗方法。我们利用我们的CTD大鼠模型开发了一种新的腺相关病毒（AAV）驱动的基因疗法，在大鼠中枢神经系统中重建功能性Slc6a8转运体。我们发现，在出生后第11天的幼崽进行小脑延髓池内注射AAV载体后，小脑、延髓和脊髓中Slc6a8-FLAG的转导以及这些脑区中Cr的部分恢复，同时完全预防了在CTD雄性大鼠中观察到的运动缺陷和心肌细胞发育受损。虽然需要更多的工作来纠正那些与前脑结构更相关的CTD表型，但这项研究首次证明了AAV驱动的基因疗法对CTD有积极作用，因此代表了一种非常令人鼓舞的方法来治疗迄今为止无法治疗的CTD。
