Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down"

被引：0

作者：

Pinyon, Jeremy L. ^{[1
,2
]}

Von Jonquieres, Georg ^{[1
]}

Crawford, Edward N. ^{[1
]}

Al Abed, Amr ^{[1
]}

Power, John M. ^{[1
]}

Klugmann, Matthias ^{[1
]}

Browne, Cherylea J. ^{[1
,3
]}

Housley, David M. ^{[1
]}

Wise, Andrew K. ^{[4
,5
]}

Fallon, James B. ^{[4
,5
]}

Shepherd, Robert K. ^{[4
,5
]}

Lin, John Y. ^{[6
]}

McMahon, Catherine ^{[7
]}

McAlpine, David ^{[7
]}

Birman, Catherine S. ^{[7
,8
,9
,10
]}

Lai, Waikong ^{[10
]}

Enke, Ya Lang ^{[11
]}

Carter, Paul M. ^{[11
]}

Patrick, James F. ^{[11
]}

Gay, Robert D. ^{[11
]}

Marie, Corinne ^{[12
,13
]}

Scherman, Daniel ^{[12
,14
]}

Lovell, Nigel H. ^{[1
]}

Housley, Gary D. ^{[1
]}

机构：

[1] UNSW, Tyree Inst Hlth Engn IHealthE, Grad Sch Biomed Engn,Dept Physiol, Sch Biomed Sci,Translat Neurosci Fac, Sydney, NSW 2052, Australia

[2] Univ Sydney, Fac Med & Hlth, Sch Med Sci, Charles Perkins Ctr, Sydney, NSW 2006, Australia

[3] Univ Western Sydney, Sch Sci, Med Sci, Sydney, NSW 2560, Australia

[4] Bion Inst, 384-388 Albert St, Melbourne, Vic 3002, Australia

[5] Univ Melbourne, Med Bion, Dept Otolaryngol, Melbourne, Vic 3002, Australia

[6] Univ Tasmania, Tasmanian Sch Med, Hobart, Tas 7001, Australia

[7] Macquarie Univ, Fac Med & Hlth Sci, Hearing Hub, Sydney, NSW 2109, Australia

[8] Univ Sydney, Fac Med & Hlth, Sydney, NSW 2109, Australia

[9] Royal Prince Alfred Hosp, Dept Otolaryngol, Camperdown, NSW 2050, Australia

[10] Royal Inst Deaf & Blind Children, NextSense, Gladesville, NSW 2111, Australia

[11] Macquarie Univ, Cochlear Ltd, Univ Ave, Macquarie Pk, NSW 2109, Australia

[12] Univ Paris Cite, INSERM, UTCBS, CNRS, F-75006 Paris, France

[13] Univ PSL, Chim ParisTech, F-75005 Paris, France

[14] Fondat Malad Rares, 96 Rue Didot, F-75014 Paris, France

来源：

ADVANCED SCIENCE | 2024年 / 11卷 / 30期

基金：

澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

CNS electrotransfer; CNS neuromodulation; nerve regeneration; nonviral gene augmentation therapy; precision gene delivery; SPIRAL GANGLION NEURONS; NEUROTROPHIC FACTOR; THERAPY; ELECTROPORATION; STIMULATION; EXPRESSION; SURVIVAL; DELIVERY; GROWTH; CORTEX;

D O I：

暂无

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

引用

页数：18

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