scholarly journals Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration

Brain ◽  
2019 ◽  
Vol 142 (2) ◽  
pp. 295-311 ◽  
Author(s):  
Ruben Eggers ◽  
Fred de Winter ◽  
Stefan A Hoyng ◽  
Rob C Hoeben ◽  
Martijn J A Malessy ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Axon Regeneration ◽  
Long Distance ◽  
Gdnf Gene ◽  
Gene Switch

scholarly journals Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy

2021 ◽  
Author(s):  
Shi Cheng ◽  
Marcel M. van Gaalen ◽  
Mathias Bähr ◽  
Enrique Garea-Rodriguez ◽  
Sebastian Kügler
Keyword(s):  
Gene Therapy ◽  
Gene Switch ◽  
Pharmacological Control

scholarly journals rab-27 acts in an intestinal pathway to inhibit axon regeneration in C. elegans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009877
Author(s):  
Alexander T. Lin-Moore ◽  
Motunrayo J. Oyeyemi ◽  
Marc Hammarlund
Keyword(s):  
Motor Neurons ◽  
Axon Regeneration ◽  
Rab Gtpase ◽  
Long Distance ◽  
Extrinsic Factors ◽  
C Elegans ◽  
Cellular Environment ◽  
Neuropeptide Secretion ◽  
Neuronal Tissues ◽  
Nervous System Function

Injured axons must regenerate to restore nervous system function, and regeneration is regulated in part by external factors from non-neuronal tissues. Many of these extrinsic factors act in the immediate cellular environment of the axon to promote or restrict regeneration, but the existence of long-distance signals regulating axon regeneration has not been clear. Here we show that the Rab GTPase rab-27 inhibits regeneration of GABAergic motor neurons in C. elegans through activity in the intestine. Re-expression of RAB-27, but not the closely related RAB-3, in the intestine of rab-27 mutant animals is sufficient to rescue normal regeneration. Several additional components of an intestinal neuropeptide secretion pathway also inhibit axon regeneration, including NPDC1/cab-1, SNAP25/aex-4, KPC3/aex-5, and the neuropeptide NLP-40, and re-expression of these genes in the intestine of mutant animals is sufficient to restore normal regeneration success. Additionally, NPDC1/cab-1 and SNAP25/aex-4 genetically interact with rab-27 in the context of axon regeneration inhibition. Together these data indicate that RAB-27-dependent neuropeptide secretion from the intestine inhibits axon regeneration, and point to distal tissues as potent extrinsic regulators of regeneration.

scholarly journals Combining timed GDNF and ChABC gene therapy to promote long‐distance regeneration following ventral root avulsion and repair

2020 ◽  
Vol 34 (8) ◽  
pp. 10605-10622 ◽  
Author(s):  
Ruben Eggers ◽  
Fred Winter ◽  
Lotte Smit ◽  
Maruelle Luimens ◽  
Elizabeth M. Muir ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Ventral Root ◽  
Root Avulsion ◽  
Long Distance ◽  
Ventral Root Avulsion

Dopaminergic Neurons Protected from Degeneration by GDNF Gene Therapy

Science ◽  
1997 ◽  
Vol 275 (5301) ◽  
pp. 838-841 ◽  
Author(s):  
D. L. Choi-Lundberg
Keyword(s):  
Gene Therapy ◽  
Dopaminergic Neurons ◽  
Gdnf Gene

scholarly journals Seizure Suppression by GDNF Gene Therapy in Animal Models of Epilepsy

2007 ◽  
Vol 15 (6) ◽  
pp. 1106-1113 ◽  
Author(s):  
Irene Kanter-Schlifke ◽  
Biljana Georgievska ◽  
Deniz Kirik ◽  
Merab Kokaia
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Gdnf Gene ◽  
Animal Models Of Epilepsy ◽  
Models Of Epilepsy ◽  
Seizure Suppression

scholarly journals rab-27 acts in an intestinal secretory pathway to inhibit axon regeneration in C. elegans

2020 ◽  
Author(s):  
Alexander T. Lin-Moore ◽  
Motunrayo J. Oyeyemi ◽  
Marc Hammarlund
Keyword(s):  
Motor Neurons ◽  
Secretory Pathway ◽  
Axon Regeneration ◽  
Rab Gtpase ◽  
Long Distance ◽  
Extrinsic Factors ◽  
C Elegans ◽  
Cellular Environment ◽  
Neuropeptide Secretion ◽  
Neuronal Tissues

ABSTRACTInjured axons must regenerate to restore nervous system function, and regeneration is regulated in part by external factors from non-neuronal tissues. Many of these extrinsic factors act in the immediate cellular environment of the axon to promote or restrict regeneration, but the existence of long-distance signals regulating axon regeneration has not been clear. Here we show that the Rab GTPase rab-27 inhibits regeneration of GABAergic motor neurons in C. elegans through activity in the intestine. Re-expression of RAB-27, but not the closely related RAB-3, in the intestine of rab-27 mutant animals is sufficient to rescue normal regeneration. Several additional components of an intestinal neuropeptide secretion pathway also inhibit axon regeneration, including NPDC1/cab-1, SNAP25/aex-4, and KPC3/aex-5. Together these data indicate that RAB-27-dependent neuropeptide secretion from the intestine inhibits axon regeneration, and point to distal tissues as potent extrinsic regulators of regeneration.

scholarly journals Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Stuart I. Hodgetts ◽  
Jun Han Yoon ◽  
Alysia Fogliani ◽  
Emmanuel A. Akinpelu ◽  
Danii Baron-Heeris ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Cortical Neurons ◽  
Viral Vector ◽  
Long Distance ◽  
Adult Rats ◽  
F344 Rat ◽  
Mesenchymal Precursor Cells ◽  
Cord Injury ◽  
Mesenchymal Precursor

Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations.

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