1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France [3] LUNAM Université, Université de Nantes, Nantes, France.
1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
Gene Ther. 2015 Apr;22(4):316-24. doi: 10.1038/gt.2014.121. Epub 2015 Jan 15.
Intracerebral administration of recombinant adeno-associated vector (AAV) has been performed in several clinical trials. However, delivery into the brain requires multiple injections and is not efficient to target the spinal cord, thus limiting its applications. To assess widespread and less invasive strategies, we tested intravenous (IV) or intrathecal (that is, in the cerebrospinal fluid (CSF)) delivery of a rAAVrh10-egfp vector in adult and neonate rats and studied the effect of the age at injection on neurotropism. IV delivery is more efficient in neonates and targets predominantly Purkinje cells of the cerebellum and sensory neurons of the spinal cord and dorsal root ganglia. A single intra-CSF administration of AAVrh10, single strand or oversized self-complementary, is efficient for the targeting of neurons in the cerebral hemispheres, cerebellum, brainstem and spinal cord. Green fluorescent protein (GFP) expression is more widespread in neonates when compared with adults. More than 50% of motor neurons express GFP in the three segments of the spinal cord in neonates and in the cervical and thoracic regions in adults. Neurons are almost exclusively transduced in neonates, whereas neurons, astrocytes and rare oligodendrocytes are targeted in adults. These results expand the possible routes of delivery of AAVrh10, a serotype that has shown efficacy and safety in clinical trials concerning neurodegenerative diseases.
脑内给予重组腺相关病毒（AAV）已在几项临床试验中进行。然而，向脑内给药需要多次注射，并且对脊髓的靶向效率不高，因此限制了其应用。为了评估广泛且侵袭性较小的策略，我们在成年和新生大鼠中测试了静脉内（IV）或鞘内（即脑脊髓液（CSF）内）给予 rAAVrh10-egfp 载体，并研究了注射时的年龄对神经营养的影响。IV 给药在新生大鼠中更有效，主要靶向小脑的浦肯野细胞和脊髓的感觉神经元及背根神经节。单次鞘内给予 AAVrh10、单链或过大自互补体，可有效靶向大脑半球、小脑、脑干和脊髓中的神经元。与成年大鼠相比，新生大鼠中的绿色荧光蛋白（GFP）表达更为广泛。在新生大鼠的三个脊髓段和成年大鼠的颈胸段中，超过 50%的运动神经元表达 GFP。在新生大鼠中，神经元几乎完全被转导，而在成年大鼠中，神经元、星形胶质细胞和罕见的少突胶质细胞被靶向。这些结果扩展了 AAVrh10 的可能给药途径，该血清型在涉及神经退行性疾病的临床试验中已显示出疗效和安全性。
