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

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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.

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