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AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord

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 t...

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Autores principales: Steward, Oswald, Coulibaly, Aminata P., Metcalfe, Mariajose, Dam, Jamie M., Yee, Kelly M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560646/
https://www.ncbi.nlm.nih.gov/pubmed/34761054
http://dx.doi.org/10.1016/j.omtm.2021.09.016
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author Steward, Oswald
Coulibaly, Aminata P.
Metcalfe, Mariajose
Dam, Jamie M.
Yee, Kelly M.
author_facet Steward, Oswald
Coulibaly, Aminata P.
Metcalfe, Mariajose
Dam, Jamie M.
Yee, Kelly M.
author_sort Steward, Oswald
collection PubMed
description 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.
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spelling pubmed-85606462021-11-09 AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord Steward, Oswald Coulibaly, Aminata P. Metcalfe, Mariajose Dam, Jamie M. Yee, Kelly M. Mol Ther Methods Clin Dev Original Article 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. American Society of Gene & Cell Therapy 2021-10-05 /pmc/articles/PMC8560646/ /pubmed/34761054 http://dx.doi.org/10.1016/j.omtm.2021.09.016 Text en © 2021 The Authors. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Steward, Oswald
Coulibaly, Aminata P.
Metcalfe, Mariajose
Dam, Jamie M.
Yee, Kelly M.
AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord
title AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord
title_full AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord
title_fullStr AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord
title_full_unstemmed AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord
title_short AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord
title_sort aav vectors accumulate in the pineal gland after injections into the brain or spinal cord
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560646/
https://www.ncbi.nlm.nih.gov/pubmed/34761054
http://dx.doi.org/10.1016/j.omtm.2021.09.016
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