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

Eggers, Ruben; Winter, Fred de; Hoyng, Stefan A.; Hoeben, Rob C.; Malessy, Martijn J. A.; Tannemaat, Martijn R.; Verhaagen, Joost

doi:10.1093/brain/awy340

Cited by 39 publications

(72 citation statements)

References 83 publications

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“…Second-generation Lentiviral (LV) vectors were produced in human embryonic kidney 293T (HEK293T) cells using a 3 plasmid co-transfection of the VSV-G envelope protein vector (pMD.G.2), the viral core packaging vector (pCMVdeltaR8.7.4), and the transfer vector plasmid (pLV-CMV-GArGFP, pLV-CMV-ChABC, pLV-TRE-GDNF, or pLV-CMV-GArrtTA) as described previously. 24,37 LV particles were harvested from the medium by ultracentrifugation and dissolved in phosphate-buffered saline (PBS, pH 7.4). By infecting HEK293T cells with a serial dilution of the LV stocks followed by a qPCR using SYBR green (Applied Biosystems) for the Woodchuck hepatitis virus posttranscriptional regulatory element, the number of viral genomic copies (GC) inserted into the host cell genomic DNA was determined .…”

Section: Production Of Lentiviral Vectorsmentioning

confidence: 99%

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

et al. 2020

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Section: Production Of Lentiviral Vectorsmentioning

confidence: 99%

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

et al. 2020

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“…Neurotrophic factors, although essential to the regeneration of an axon, must be delivered in a controlled manner. For example, excess levels of GDNF can be detrimental to nerve repair, causing nerve sprouting and axon entrapment [66]. Neurotrophic factors have potential to be delivered as a drug, although gene edited cell therapies that allow controlled release of neurotrophic factors are an attractive option.…”

Section: Creating a Tissue Microenvironment That Supports Regenerationmentioning

confidence: 99%

“…Neurotrophic factors have potential to be delivered as a drug, although gene edited cell therapies that allow controlled release of neurotrophic factors are an attractive option. By combining expression of specific neurotrophic factors such as GDNF [66] or the upstream transcription factor c-Jun [67•] with a Tet-On/Tet-Off system, the delivery can be carefully controlled to avoid overexpression and off-target reinnervation [66].…”

Section: Creating a Tissue Microenvironment That Supports Regenerationmentioning

confidence: 99%

Strategies for Peripheral Nerve Repair

Wilcox

Gregory

Powell

et al. 2020

Curr. Tissue Microenviron. Rep.

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Purpose of Review This review focuses on biomechanical and cellular considerations required for development of biomaterials and engineered tissues suitable for implantation following PNI, as well as translational requirements relating to outcome measurements for testing success in patients. Recent Findings Therapies that incorporate multiple aspects of the regenerative environment are likely to be key to improving therapies for nerve regeneration. This represents a complex challenge when considering the diversity of biological, chemical and mechanical factors involved. In addition, clinical outcome measures following peripheral nerve repair which are sensitive and responsive to changes in the tissue microenvironment following neural injury and regeneration are required. Summary Effective new therapies for the treatment of PNI are likely to include engineered tissues and biomaterials able to evoke a tissue microenvironment that incorporates both biochemical and mechanical features supportive to regeneration. Translational development of these technologies towards clinical use in humans drives a concomitant need for improved clinical measures to quantify nerve regeneration.

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“…In gene therapy paradigms using GFL [8,84], our assumption is that transgene expression should be controlled in order to avoid aberrant sprouting and perpetuation of neuroinflammatory processes which can become deleterious. Clinically-acceptable genetic switches are becoming available and could improve the outcome of future clinical trials with GFL [85][86][87][88][89][90][91][92].…”

Section: Conclusion and Further Prospectsmentioning

confidence: 99%

GDNF, a Neuron-derived Factor Upregulated in Glial Cells during Disease

Azevedo¹,

Sander²,

Tenenbaum³

2019

Preprint

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In healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons and in some instances, it has furthermore been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with GDNF family receptor α1 (GFRα1) which is mainly expressed by neurons and can act in cis as a membrane-bound or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interaction with RET (“rearranged during transfection”) or with a lower affinity with neural cell adhesion molecule (NCAM). GDNF can also signal independently from GFRα1 via interaction with syndecan-3. RET being expressed by neurons involved in several pathways: nigro-striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc. could be the main determinant of the specificity of GDNF pro-survival effect. In injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive neural stem cells and neuron/glia (NG2) progenitors. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cells activation. Some reports also describe upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation.

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

Cited by 39 publications

References 83 publications

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

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

Strategies for Peripheral Nerve Repair

GDNF, a Neuron-derived Factor Upregulated in Glial Cells during Disease

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