Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders
Genetic disorders of the central nervous system (CNS) comprise a significant portion of disability in both children and adults. Several preclinical animal models have shown effective adeno-associated virus (AAV) mediated gene transfer for either treatment or prevention of autosomal recessive genetic...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/2/1050 |
| _version_ | 1797339850241736704 |
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| author | Rrita Daci Terence R. Flotte |
| author_facet | Rrita Daci Terence R. Flotte |
| author_sort | Rrita Daci |
| collection | DOAJ |
| description | Genetic disorders of the central nervous system (CNS) comprise a significant portion of disability in both children and adults. Several preclinical animal models have shown effective adeno-associated virus (AAV) mediated gene transfer for either treatment or prevention of autosomal recessive genetic disorders. Owing to the intricacy of the human CNS and the blood–brain barrier, it is difficult to deliver genes, particularly since the expression of any given gene may be required in a particular CNS structure or cell type at a specific time during development. In this review, we analyzed delivery methods for AAV-mediated gene therapy in past and current clinical trials. The delivery routes analyzed were direct intraparenchymal (IP), intracerebroventricular (ICV), intra-cisterna magna (CM), lumbar intrathecal (IT), and intravenous (IV). The results demonstrated that the dose used in these routes varies dramatically. The average total doses used were calculated and were 1.03 × 10<sup>13</sup> for IP, 5.00 × 10<sup>13</sup> for ICV, 1.26 × 10<sup>14</sup> for CM, and 3.14 × 10<sup>14</sup> for IT delivery. The dose for IV delivery varies by patient weight and is 1.13 × 10<sup>15</sup> IV for a 10 kg infant. Ultimately, the choice of intervention must weigh the risk of an invasive surgical procedure to the toxicity and immune response associated with a high dose vector. |
| first_indexed | 2024-03-08T09:53:23Z |
| format | Article |
| id | doaj.art-f5fa8b8aac5341e8ab322998911b827a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T09:53:23Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f5fa8b8aac5341e8ab322998911b827a2024-01-29T13:56:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-01252105010.3390/ijms25021050Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene DisordersRrita Daci0Terence R. Flotte1Department of Neurosurgery, University of Massachusetts Chan Medical School, 55 N Lake Ave, Worcester, MA 01655, USAHorae Gene Therapy Center, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USAGenetic disorders of the central nervous system (CNS) comprise a significant portion of disability in both children and adults. Several preclinical animal models have shown effective adeno-associated virus (AAV) mediated gene transfer for either treatment or prevention of autosomal recessive genetic disorders. Owing to the intricacy of the human CNS and the blood–brain barrier, it is difficult to deliver genes, particularly since the expression of any given gene may be required in a particular CNS structure or cell type at a specific time during development. In this review, we analyzed delivery methods for AAV-mediated gene therapy in past and current clinical trials. The delivery routes analyzed were direct intraparenchymal (IP), intracerebroventricular (ICV), intra-cisterna magna (CM), lumbar intrathecal (IT), and intravenous (IV). The results demonstrated that the dose used in these routes varies dramatically. The average total doses used were calculated and were 1.03 × 10<sup>13</sup> for IP, 5.00 × 10<sup>13</sup> for ICV, 1.26 × 10<sup>14</sup> for CM, and 3.14 × 10<sup>14</sup> for IT delivery. The dose for IV delivery varies by patient weight and is 1.13 × 10<sup>15</sup> IV for a 10 kg infant. Ultimately, the choice of intervention must weigh the risk of an invasive surgical procedure to the toxicity and immune response associated with a high dose vector.https://www.mdpi.com/1422-0067/25/2/1050gene therapyadeno-associated virus vectorAAVgene deliveryinherited disorders |
| spellingShingle | Rrita Daci Terence R. Flotte Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders International Journal of Molecular Sciences gene therapy adeno-associated virus vector AAV gene delivery inherited disorders |
| title | Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders |
| title_full | Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders |
| title_fullStr | Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders |
| title_full_unstemmed | Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders |
| title_short | Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders |
| title_sort | delivery of adeno associated virus vectors to the central nervous system for correction of single gene disorders |
| topic | gene therapy adeno-associated virus vector AAV gene delivery inherited disorders |
| url | https://www.mdpi.com/1422-0067/25/2/1050 |
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