ArticleHuman gene therapy2018
Design of a Novel Gene Therapy Construct to Achieve Sustained Brain-Derived Neurotrophic Factor Signaling in Neurons.
Article in Human gene therapy, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays.International journal of molecular sciences · 2020Pooled it
- Design and initial characterization of a novel mini-promoter for gene therapies targeting the central nervous system.Molecular therapy. Advances · 2026Article
- Characterization of adeno-associated viral transduction of retinal ganglion cells in adult and old mice.Molecular therapy. Methods & clinical development · 2025Article
- Dose-ranging and further therapeutic evaluation of a bicistronic humanized TrkB-BDNF gene therapy for glaucoma in rodents.Molecular neurodegeneration advances · 2025Article
- Challenging glaucoma with emerging therapies: an overview of advancements against the silent thief of sight.Frontiers in medicine · 2025Review
- Intramuscular Injection of rAAV2-retro for Low Motor Neuron Transduction: Evaluating Five Promoters.International journal of medical sciences · 2025Article
- Gene therapy for glaucoma: Targeting key mechanisms.Vision research · 2024Review
- Advances in Neuroprotection in Glaucoma: Pharmacological Strategies and Emerging Technologies.Pharmaceuticals (Basel, Switzerland) · 2024Review
- The concept of gene therapy for glaucoma: the dream that has not come true yet.Neural regeneration research · 2024Review
- OPA1 Dominant Optic Atrophy: Pathogenesis and Therapeutic Targets.Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society · 2023Article
- Improving adeno-associated viral (AAV) vector-mediated transgene expression in retinal ganglion cells: comparison of five promoters.Gene therapy · 2023Article
- Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Evaluation of the SH-SY5Y cell line as anFrontiers in molecular neuroscience · 2023Article
- Simultaneous PET/MRI: The future gold standard for characterizing motor neuron disease-A clinico-radiological and neuroscientific perspective.Frontiers in neurology · 2022Review
- A Review on Mesenchymal Stem Cells for Treatment of Retinal Diseases.Stem cell reviews and reports · 2021Review
- Extraocular, periocular, and intraocular routes for sustained drug delivery for glaucoma.Progress in retinal and eye research · 2021Review
- Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions.Biomolecules · 2021Review
- Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axonal transport with functional recovery.Science advances · 2021Article
- Review
- Immunological and molecular basics of the primary open angle glaucoma pathomechanism.Central-European journal of immunology · 2021Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related receptor-B (TrkB) is an important signaling system for the maintenance and survival of neurons. Gene therapy using either recombinant adeno-associated virus (AAV) or lentiviral vectors can provide sustained delivery of BDNF to tissues where reduced BDNF signaling is hypothesized to contribute to disease pathophysiology. However, elevation in BDNF at target sites has been shown to lead to a downregulation of TrkB receptors, thereby reducing the effect of chronic BDNF delivery over time. A novel gene sequence has been designed coding both the ligand (BDNF) and the TrkB receptor in a single transgene separated by a short viral-2A sequence. The single transgene is efficiently processed intracellularly in vitro and in vivo to yield the two mature proteins, which are then independently transported to their final cellular locations: TrkB receptors to the cell surface, and BDNF contained within secretory vesicles. To accommodate the coding sequences of both BDNF and TrkB receptors within the narrow confines of the AAV vectors (4.7 kb pairs), the coding region for the pro-domain of BDNF was removed and the signal peptide sequence modified to improve production, intracellular transport, and secretion of mature BDNF (mBDNF). Intracellular processing and efficacy was shown in HEK293 cells and SH-SY5Y neuroblastoma cells using plasmid DNA and after incorporating the TrkB-2A-mBDNF into an AAV2 vector. Increased BDNF/TrkB-mediated intracellular signaling pathways were observed after AAV2 vector transfection while increased TrkB phosphorylation could be detected in combination with neuroprotection from hydrogen peroxide-induced oxidative stress. Correct processing was also shown in vivo in mouse retinal ganglion cells after AAV2 vector administration to the eye. This novel construct is currently being investigated for its efficacy in animal models to determine its potential to progress to human clinical studies in the future.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.