Direct Convective Delivery for Nervous System Gene Therapy





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








  • Central nervous system convection-enhanced delivery of gene therapy provides targeted uniform distribution of viral vectors carrying therapeutic genes in the brain.



  • Viral vectors serve as delivery vehicles for gene therapy and are selected based on cellular trophism and axonal transport features.



  • 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.



Table 1

Current neurodegenerative disorder clinical trials involving parenchymal delivery of viral vector gene therapy




























































































































































































































Neurodegenerative Disease NCT Number Phases Study Start Transgene Target Viral Vector
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

Abbreviations: AADC, Aromatic l -amino acid decarboxylase; BDNF, brain-derived neurotrophic factor; GAD, glutamic acid decarboxylase; GBA, glucosylceramidase beta; GDNF, glial-derived neurotrophic factor; GTPCH, guanosine triphosphate cyclohydrolase; HTT, huntingtin; NTN, neurturin; SN, substantia nigra; STN, subthalamic nucleus; TH, tyrosine hydroxylase; VTA, ventral tegmental area.


Table 2

Current gene therapy trials for metabolic disorders that involve direct brain delivery of viral vectors to parenchymal white matter



















































































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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Jul 6, 2025 | Posted by in NEUROSURGERY | Comments Off on Direct Convective Delivery for Nervous System Gene Therapy

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