Convection-enhanced delivery for central nervous system gene therapy is an emerging treatment strategy to modify the course of previously untreatable or inadequately treated neurologic conditions, including brain tumors, metabolic disorders, epilepsy, and neurodegenerative disorders. Ongoing nervous system gene therapy clinical trials highlight advantages and ongoing challenges to this therapeutic paradigm.
Key points
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Central nervous system convection-enhanced delivery of gene therapy provides targeted uniform distribution of viral vectors carrying therapeutic genes in the brain.
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Viral vectors serve as delivery vehicles for gene therapy and are selected based on cellular trophism and axonal transport features.
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Gene therapy for neurologic disorders has potential to modify the course of currently untreatable diseases.
Introduction
Direct convection-enhanced delivery (CED) is increasingly used to deliver gene therapy to the nervous system. The unique properties of convective delivery, or “ bulk flow ,” can be exploited to treat diseased neuronal circuits with in the central nervous system (CNS). Specifically, convective perfusion of targeted regions with viral vectors carrying therapeutic genes can be performed within the nervous system in a safe, reliable, and homogeneous manner across the blood–brain barrier. The use of convective perfusion of diseased neuronal circuits with therapeutic genes provides the opportunity to treat neurologic disorders that are ineffectively treated or not treatable using current therapeutic (medical and surgical) paradigms. We describe the biologic features of nervous system gene therapy, convective delivery paradigms, and ongoing clinical trials of this emerging neurosurgical treatment.
Gene therapy in the nervous system
Mechanism of Action
Improved understanding of the genetic mechanisms underlying disease pathology has allowed for the development of therapeutic gene targets. These “gene therapy” strategies offer treatment for the “root cause” of a disease in a single permanent treatment. Nervous system gene therapy involves the delivery of nucleic acid genomic material to specific anatomic targets in the CNS. Currently, viral vectors are used as carriers of therapeutic transgenes to nervous system target cells, such as neurons and astrocytes. The viral vectors carrying the therapeutic gene are actively taken up (transfection) by the nervous system cells. After transfection, the transcriptional unit is capable of promotor regulated expression of therapeutic molecules (eg, proteins and microRNA) intended to replace lost function (enzyme activity), increase existing function/regeneration (neurotrophic factors) or suppress unwanted function (mutant protein accumulation). , Different viral vectors used in CNS gene therapy have defined capabilities, including maximal genetic payload, cellular trophism, and axonal transport. These characteristics are the basis for the selection of viral vector in preclinical development.
Viral Vectors
Adeno-associated virus (AAV) vectors are the most frequently used genetic carrier in gene therapy for CNS disorders. Currently, 87% of CNS gene therapy trials use an AAV viral vector for treatment ( Tables 1 and 2 ). AAVs are small, nonreplicating and nonpathogenic vectors capable of transfecting nondividing cells and exhibit strong neuronal trophism. After cellular transfection with AAVs, the transgene typically does not integrate into host genome but instead forms an extrachromosomal episome. Gene expression can persist for decades in postmitotic cells such as neurons. AAV2 is the most common serotype in neurodegenerative disorder trials (see Table 1 ) due to its selective neuronal trophism and antegrade axonal transport with capability for vector transport along axonal connections to distal CNS structures. Other AAV serotypes, including as AAV5 and AAV9, can be transported retrograde from the site of infusion. AAV serotype-associated cellular trophism among AAV serotypes is based on cell-type specific surface receptors responsible for viral transfection. Although delivery vehicles in CNS gene therapy are selected for their cellular tropism, the use of promotors can enhance cell-specific gene expression.
Neurodegenerative Disease | NCT Number | Phases | Study Start | Transgene | Target | Viral Vector |
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Parkinson’s Disease | NCT00195143 | 1 | 2003 | GAD | STN | AAV2 |
Parkinson’s Disease | NCT00229736 | 1 | 2004 | AADC | Putamen | AAV2 |
Parkinson’s Disease | NCT00627588 | 1/2 | 2008 | AADC, TH, GTPCH | Striatum | LV |
Parkinson’s Disease | NCT00643890 | 2 | 2008 | GAD | STN | AAV2 |
Parkinson’s Disease | NCT01621581 | 1 | 2013 | GDNF | Striatum | AAV2 |
Parkinson’s Disease | NCT01973543 | 1 | 2013 | AADC | Striatum | AAV2 |
Parkinson’s Disease | NCT02418598 | 1/2 | 2015 | AADC | Putamen | AAV2 |
Parkinson’s Disease | NCT03065192 | 1 | 2017 | AADC | Striatum | AAV2 |
Parkinson’s Disease | NCT03562494 | 1 | 2018 | AADC | Putamen | AAV2 |
Parkinson’s Disease | NCT03720418 | 1/2 | 2018 | AADC, TH, GTPCH | Putamen | LV |
Parkinson’s Disease | NCT04167540 | 1 | 2020 | GDNF | Putamen | AAV2 |
Parkinson’s Disease | NCT05603312 | 1/2 | 2022 | GAD | STN | AAV2 |
Parkinson’s Disease | NCT05894343 | 1/2 | 2023 | GAD | STN | AAV2 |
Parkinson’s Disease | NCT06285643 | 2 | 2024 | GDNF | Putamen | AAV2 |
AADC deficiency | NCT01395641 | 1/2 | 2014 | AADC | Putamen | AAV2 |
AADC deficiency | NCT02852213 | 1 | 2016 | AADC | SN/VTA | AAV2 |
AADC deficiency | NCT02926066 | 2 | 2016 | AADC | Putamen | AAV2 |
AADC deficiency | NCT04903288 | 2 | 2021 | AADC | Putamen | AAV2 |
AADC deficiency | NCT05765981 | 1 | 2023 | AADC | Putamen | AAV9 |
AADC deficiency | NCT06432140 | 1 | 2024 | AADC | Putamen | AAV9 |
Alzheimer’s disease | NCT05040217 | 1 | 2022 | BDNF | Entorhinal cortex | AAV2 |
Huntington’s disease | NCT04120493 | 1/2 | 2019 | Huntingtin | Striatum | AAV5 |
Huntington’s disease | NCT05243017 | 1/2 | 2021 | Huntingtin | Striatum | AAV5 |
Huntington’s disease | NCT05541627 | 1/2 | 2022 | Cholesterol 24-hydroxylase | Striatum | AAVrh10 |
MSA | NCT04680065 | 1 | 2023 | GDNF | Putamen | AAV2 |
Frontotemporal dementia | NCT06064890 | 1/2 | 2023 | PGRN | Thalamus | AAV9 |
Metabolic Disease | NCT Number | Phase | Study Start | Transgene | Viral Vector | Outcome |
---|---|---|---|---|---|---|
NCL | NCT00151216 | 1 | 2004 | CLN2 | AAV2 | Reduced rate of neurologic decline measured by modified Hamburg LINCL clinical rating scale |
NCL | NCT01161576 | 1 | 2010 | CLN2 | AAVrh.10 | Treatment slowed disease. Treated cohort had 1.3–2.6-fold increase in CSF TPP1; 42.4% reduction in rate of motor decline and 47.5% reduction in rate of language decline compared with natural history cohort |
NCL | NCT01414985 | 1/2 | 2010 | CLN2 | AAVrh.10 | |
MPS IIIA | NCT01474343 | 1/2 | 2011 | SGSH | AAVrh.10 | Moderate improvements in behavior and sleep; Youngest patients derived most benefit |
MPS IIIB | NCT03300453 | 1/2 | 2013 | NAGlU | AAV2/5 | Neurocognition improved in all patients; Youngest patient neurologic function near normal; NAGLU activity 15%–20% of normal; Enzyme production in brain persists at 5 y |
MPS IIIA | NCT03612869 | 2/3 | 2018 | SGSH | AAVrh.10 | Pending |
MLD | NCT01801709 | 1/2 | 2014 | ARSA | AAVrh.10 | Four patients treated, all presymptomatic or early-symptomatic; ARSA activity in CSF undetectable before treatment reached 20%–70% of normal after treatment in dose-dependent manner; symptoms progressed in a similar manner to natural history of disease |
ALD | NCT03727555 | 1/2 | 2018 | ABCD1 | LV | Pending |
MLD | NCT03725670 | 1/2 | 2018 | ARSA | LV | Pending |

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