AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord.
AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord.
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AAV 载体注射到大脑或脊髓后会在松果体中积聚。
DOI：
10.1016/j.omtm.2021.09.016
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发表时间：
2021-12-10
期刊：
影响因子：
--
通讯作者：
Yee KM
中科院分区：
文献类型：
--
作者：
Steward O;Coulibaly AP;Metcalfe M;Dam JM;Yee KM
AAV载体被广泛用于神经系统疾病的基因修饰疗法。在这里，我们报告了令人惊讶的发现，即将不同的AAV注射到脑、脊髓或脑脊液（CSF）中导致松果体中细胞的稳健转导。我们记录了将AAV 2/9-shPTEN-zsGreen局部注射到大鼠的感觉运动或海马中以及将AAV 2/Cre注射到具有stop-flox tdT报告基因的转基因小鼠的脊髓中后松果体中细胞的转导。甚至当将AAV 2/Cre注射到距离松果体许多毫米的腰脊髓中时，松果体转导也是明显的。免疫组化染色的细胞类型的抗体在松果体显示，松果体细胞被转导。还用脑室内（i. c. v.）注射AAV 2/9-shPTEN-zsGreen后，表明在将AAV局灶性注射到CNS实质中后的松果体转导可能是由载体从注射部位扩散到CSF中然后在松果体中积累引起的。总而言之，这些发现表明需要警惕治疗性腺相关病毒在松果体中的脱靶积累以及腺相关病毒驱动的治疗性物质在松果体细胞中的表达所造成的功能后果和可能的不良影响。我们报告了令人惊讶的发现，即注射到脑、脊髓或脑脊液（CSF）中的不同AAV在松果体和松果体细胞中积累。这些发现表明，需要警惕的功能后果和可能的不良影响，松果体转导治疗性AAV注射到中枢神经系统。
AAV vectors are being used extensively for gene-modifying therapies for neurological disorders. Here, we report the surprising discovery that injections of different AAVs into the brain, spinal cord, or cerebrospinal fluid (CSF) lead to robust transduction of cells in the pineal gland. We document transduction of cells in the pineal gland following focal injections of AAV2/9-shPTEN-zsGreen into the sensorimotor or hippocampus of rats and injections of AAV2/Cre into the spinal cord of transgenic mice with a stop-flox tdT reporter. Pineal transduction was evident even when AAV2/Cre injections were made into the lumbar spinal cord many millimeters distant from the pineal gland. Immunostaining with antibodies for cell types in the pineal gland revealed that pinealocytes were transduced. Pineal transduction was also observed with intracerebroventricular (i.c.v.) injections of AAV2/9-shPTEN-zsGreen, suggesting that pineal transduction following focal injections of AAV into CNS parenchyma may be caused by diffusion of the vector from the injection sites into the CSF and then accumulation in the pineal gland. Together, these findings suggest the need for vigilance for functional consequences and possible adverse effects of off-target accumulation of therapeutic AAVs in the pineal gland and AAV-driven expression of therapeutic cargos in pinealocytes. We report the surprising discovery that different AAVs injected into the brain, spinal cord, or cerebrospinal fluid (CSF) accumulate in the pineal gland and transduce pinealocytes. These findings suggest the need for vigilance for functional consequences and possible adverse effects of pineal transduction by therapeutic AAVs injected into the CNS.
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影响因子：
5.3
作者：
Steward, Oswald;Sharp, Kelli G.;Bonner, Joseph F.
通讯作者：
Bonner, Joseph F.
脑膜淋巴系统：神经生理学的新玩家。
影响因子：
16.2
作者：
Da Mesquita S;Fu Z;Kipnis J
通讯作者：
Kipnis J
影响因子：
16.2
作者：
Tervo DG;Hwang BY;Viswanathan S;Gaj T;Lavzin M;Ritola KD;Lindo S;Michael S;Kuleshova E;Ojala D;Huang CC;Gerfen CR;Schiller J;Dudman JT;Hantman AW;Looger LL;Schaffer DV;Karpova AY
通讯作者：
Karpova AY
影响因子：
1.6
作者：
Park JH;Hong YK
通讯作者：
Hong YK
影响因子：
5.3
作者：
Steward O;Coulibaly AP;Metcalfe M;Yonan JM;Yee KM
通讯作者：
Yee KM