Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model
Authors
Taghian, TolooHorn, Erin
Shazeeb, Mohammed S.
Bierfeldt, Lindsey J.
Tuominen, Susan M.
Koehler, Jennifer
Fernau, Deborah
Bertrand, Stephanie
Frey, Stephen
Cataltepe, Oguz
Gounis, Matthew J.
Abayazeed, Aly
Flotte, Terence R.
Sena-Esteves, Miguel
Gray-Edwards, Heather L
UMass Chan Affiliations
Department of NeurologyDepartment of Pediatrics
Department of Neurological Surgery
Department of Animal Medicine
Department of Radiology
Horae Gene Therapy Center
Document Type
Journal ArticlePublication Date
2020-06-01Keywords
GM2 gangliosidosesSandhoff
Tay-Sachs
intraparenchymal injection
thalamic injection
thalamic pain syndrome
Animal Experimentation and Research
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Nervous System Diseases
Neurology
Radiology
Therapeutics
Metadata
Show full item recordAbstract
Thalamic infusion of adeno-associated viral (AAV) vectors has been shown to have therapeutic effects in neuronopathic lysosomal storage diseases. Preclinical studies in sheep model of Tay-Sachs disease demonstrated that bilateral thalamic injections of AAV gene therapy are required for maximal benefit. Translation of thalamic injection to patients carries risks in that (1) it has never been done in humans, and (2) dosing scale-up based on brain weight from animals to humans requires injection of larger volumes. To increase the safety margin of this infusion, a flexible cannula was selected to enable simultaneous bilateral thalamic infusion in infants while monitoring by imaging and/or to enable awake infusions for injection of large volumes at low infusion rates. In this study, we tested various infusion volumes (200-800 muL) and rates (0.5-5 muL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for approximately 1 month postinjection with magnetic resonance imaging (MRI) performed at 14 and 28 days. T1-weighted MRI was used to quantify thalamic damage followed by histopathological assessment of the brain. Trends in data show that infusion volumes of 800 muL (2 x the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26 h) could have contributed to the generation of larger lesions. The target volume (400 muL, projected to be sufficient to cover most of the sheep thalamus) created the smallest lesion size. Cannula placement alone did result in damage, but this is likely associated with an inherent limitation of its use in a small brain due to the length of the distal rigid portion and lack of stable fixation. An injection rate of 5 muL/min at a volume approximately 1/3 of the thalamus (400-600 muL) appears to be well tolerated in sheep both clinically and histopathologically.Source
Taghian T, Horn E, Shazeeb MS, Bierfeldt LJ, Tuominen SM, Koehler J, Fernau D, Bertrand S, Frey S, Cataltepe OI, Gounis MJ, Abayazeed AH, Flotte TR, Sena-Esteves M, Gray-Edwards HL. Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model. Hum Gene Ther. 2020 Jun;31(11-12):617-625. doi: 10.1089/hum.2019.288. Epub 2020 May 29. PMID: 32363942. Link to article on publisher's site
DOI
10.1089/hum.2019.288Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48433PubMed ID
32363942Related Resources
ae974a485f413a2113503eed53cd6c53
10.1089/hum.2019.288