Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration
Preclinical studies have demonstrated that a single injection of an adeno-associated virus (AAV) vector into the cerebrospinal fluid (CSF) can achieve widespread gene transfer throughout the central nervous system. Successfully translating this approach to humans requires identifying factors that in...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050120300723 |
| _version_ | 1818115235207184384 |
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| author | Christian Hinderer Nathan Katz Cecilia Dyer Tamara Goode Julia Johansson Peter Bell Laura Richman Elizabeth Buza James M. Wilson |
| author_facet | Christian Hinderer Nathan Katz Cecilia Dyer Tamara Goode Julia Johansson Peter Bell Laura Richman Elizabeth Buza James M. Wilson |
| author_sort | Christian Hinderer |
| collection | DOAJ |
| description | Preclinical studies have demonstrated that a single injection of an adeno-associated virus (AAV) vector into the cerebrospinal fluid (CSF) can achieve widespread gene transfer throughout the central nervous system. Successfully translating this approach to humans requires identifying factors that influence AAV distribution in the CSF so that optimal parameters can be replicated in the clinic. In the context of developing a motor neuron-targeted gene therapy for spinal muscular atrophy, we conducted studies in nonhuman primates to evaluate the impact of injection volume on spinal cord transduction after AAV delivery via lumbar puncture. Lumbar injection of an AAVhu68 vector targeted motor neurons throughout the spinal cord, but only in juvenile nonhuman primates administered large injection volumes, equivalent to about half of the total CSF volume. Upon repeating this study with clinically relevant injection volumes and larger animals, we found that lumbar puncture failed to achieve significant transduction of the spinal cord. In contrast, vector administered into the cisterna magna distributed reproducibly throughout the spinal cord in both juvenile and adult animals. These findings highlight the challenges of translating AAV delivery via lumbar puncture to humans and suggest that delivery into the cisterna magna may represent a more feasible alternative. |
| first_indexed | 2024-12-11T04:03:24Z |
| format | Article |
| id | doaj.art-8162add8381d4358846b1c4b48a12437 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-11T04:03:24Z |
| publishDate | 2020-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-8162add8381d4358846b1c4b48a124372022-12-22T01:21:34ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-06-0117969974Translational Feasibility of Lumbar Puncture for Intrathecal AAV AdministrationChristian Hinderer0Nathan Katz1Cecilia Dyer2Tamara Goode3Julia Johansson4Peter Bell5Laura Richman6Elizabeth Buza7James M. Wilson8Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAGene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author: James M. Wilson, Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, 125 S. 31st Street, Suite 1200 TRL, Philadelphia, PA 19104-3403, USA.Preclinical studies have demonstrated that a single injection of an adeno-associated virus (AAV) vector into the cerebrospinal fluid (CSF) can achieve widespread gene transfer throughout the central nervous system. Successfully translating this approach to humans requires identifying factors that influence AAV distribution in the CSF so that optimal parameters can be replicated in the clinic. In the context of developing a motor neuron-targeted gene therapy for spinal muscular atrophy, we conducted studies in nonhuman primates to evaluate the impact of injection volume on spinal cord transduction after AAV delivery via lumbar puncture. Lumbar injection of an AAVhu68 vector targeted motor neurons throughout the spinal cord, but only in juvenile nonhuman primates administered large injection volumes, equivalent to about half of the total CSF volume. Upon repeating this study with clinically relevant injection volumes and larger animals, we found that lumbar puncture failed to achieve significant transduction of the spinal cord. In contrast, vector administered into the cisterna magna distributed reproducibly throughout the spinal cord in both juvenile and adult animals. These findings highlight the challenges of translating AAV delivery via lumbar puncture to humans and suggest that delivery into the cisterna magna may represent a more feasible alternative.http://www.sciencedirect.com/science/article/pii/S2329050120300723AAVcentral nervous systemintrathecalcerebrospinal fluidlumbar puncturecisterna magna |
| spellingShingle | Christian Hinderer Nathan Katz Cecilia Dyer Tamara Goode Julia Johansson Peter Bell Laura Richman Elizabeth Buza James M. Wilson Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration Molecular Therapy: Methods & Clinical Development AAV central nervous system intrathecal cerebrospinal fluid lumbar puncture cisterna magna |
| title | Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration |
| title_full | Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration |
| title_fullStr | Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration |
| title_full_unstemmed | Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration |
| title_short | Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration |
| title_sort | translational feasibility of lumbar puncture for intrathecal aav administration |
| topic | AAV central nervous system intrathecal cerebrospinal fluid lumbar puncture cisterna magna |
| url | http://www.sciencedirect.com/science/article/pii/S2329050120300723 |
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