Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model
Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repea...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123001614 |
| _version_ | 1797653612178964480 |
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| author | Hector Ribeiro Benatti Rachel D. Prestigiacomo Toloo Taghian Rachael Miller Robert King Matthew J. Gounis Ugur Celik Stephanie Bertrand Susan Tuominen Lindsey Bierfeldt Elizabeth Parsley Jillian Gallagher Erin F. Hall Abigail W. McElroy Miguel Sena-Esteves Anastasia Khvorova Neil Aronin Heather L. Gray-Edwards |
| author_facet | Hector Ribeiro Benatti Rachel D. Prestigiacomo Toloo Taghian Rachael Miller Robert King Matthew J. Gounis Ugur Celik Stephanie Bertrand Susan Tuominen Lindsey Bierfeldt Elizabeth Parsley Jillian Gallagher Erin F. Hall Abigail W. McElroy Miguel Sena-Esteves Anastasia Khvorova Neil Aronin Heather L. Gray-Edwards |
| author_sort | Hector Ribeiro Benatti |
| collection | DOAJ |
| description | Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2 months and will be tested for up to a year in ongoing studies. |
| first_indexed | 2024-03-11T16:47:05Z |
| format | Article |
| id | doaj.art-47746a402a8d49c9b29336720b82daae |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-11T16:47:05Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-47746a402a8d49c9b29336720b82daae2023-10-22T04:49:13ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-12-0131101122Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal modelHector Ribeiro Benatti0Rachel D. Prestigiacomo1Toloo Taghian2Rachael Miller3Robert King4Matthew J. Gounis5Ugur Celik6Stephanie Bertrand7Susan Tuominen8Lindsey Bierfeldt9Elizabeth Parsley10Jillian Gallagher11Erin F. Hall12Abigail W. McElroy13Miguel Sena-Esteves14Anastasia Khvorova15Neil Aronin16Heather L. Gray-Edwards17Horae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA; Department of Radiology, UMass Chan Medical School, 55 N Lake Ave, Worcester, MA 01655, USADepartment of Endocrinology, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA; RNA Therapeutic Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USADepartment of Radiology, UMass Chan Medical School, 55 N Lake Ave, Worcester, MA 01655, USADepartment of Radiology, UMass Chan Medical School, 55 N Lake Ave, Worcester, MA 01655, USACenter for Clinical Research, UMass Chan Medical School, 55 N Lake Ave, Worcester MA 01655, USACummings School of Veterinary Medicine, Tufts University, Grafton MA 01536, USADepartment of Animal Medicine, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USADepartment of Animal Medicine, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USACummings School of Veterinary Medicine, Tufts University, Grafton MA 01536, USAHorae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA; Department of Neurology, UMass Chan Medical School, 368 Plantation Street, Worcester MA 01605, USARNA Therapeutic Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USADepartment of Endocrinology, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA; RNA Therapeutic Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA; Department of Radiology, UMass Chan Medical School, 55 N Lake Ave, Worcester, MA 01655, USA; Corresponding author: Heather L. Gray-Edwards, UMass Chan Medical School, 368 Plantation Street, ASC6-2041, Worcester, MA 01605, USA.Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2 months and will be tested for up to a year in ongoing studies.http://www.sciencedirect.com/science/article/pii/S2329050123001614oligonucleotide safety assessmentlarge animal modelCNS drug administrationCSF drug deliveryi.c.v. injectionOmmaya reservoir |
| spellingShingle | Hector Ribeiro Benatti Rachel D. Prestigiacomo Toloo Taghian Rachael Miller Robert King Matthew J. Gounis Ugur Celik Stephanie Bertrand Susan Tuominen Lindsey Bierfeldt Elizabeth Parsley Jillian Gallagher Erin F. Hall Abigail W. McElroy Miguel Sena-Esteves Anastasia Khvorova Neil Aronin Heather L. Gray-Edwards Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model Molecular Therapy: Methods & Clinical Development oligonucleotide safety assessment large animal model CNS drug administration CSF drug delivery i.c.v. injection Ommaya reservoir |
| title | Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model |
| title_full | Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model |
| title_fullStr | Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model |
| title_full_unstemmed | Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model |
| title_short | Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model |
| title_sort | awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model |
| topic | oligonucleotide safety assessment large animal model CNS drug administration CSF drug delivery i.c.v. injection Ommaya reservoir |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123001614 |
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