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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The advantage of regulating an endogenous gene by this approach is that it mimics the way a cell normally regulates gene expression, and so should be highly efficacious and relatively free of off-target effects. For example, the company has worked on an engineered ZFP-based transcription factor potentially capable of up-regulating the gene for Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor that has the potential to slow or halt the progression of Parkinson’s disease. A ZFP-based agent of this type may be able to up-regulate this gene, thus potentially increasing production of the patient’s own GDNF protein and avoiding potential immunogenicity issues associated with administering recombinant protein. The company has also investigated the use of ZFP-based agents to down-regulate or ablate gene expression. Examples that the company have worked on include repression of the pain receptors Trk-A and PN3 for neuropathic pain, and targets in other diseases, including hemophilia, Huntington’s disease, hemoglobinopathies, lysosomal storage disorders, and Alzheimer’s disease.
Neurotrophic Factors
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
Glial cell line-derived neurotrophic factor (GDNF) is a distant member of the transforming growth factor-β superfamily,47 but apparently has a narrower range of target cells and activities. Because of its initially perceived relative specificity and its relatively high potency, GDNF has received much attention in the neurotrophic factor field. GDNF is a ∼134-amino, ∼15- to 20-kDa protein that acts as a homodimer. GDNF synthesis is not unique to the nervous system, in fact, its expression levels are much higher in many peripheral organs during development, and in lung, liver, and ovary during adulthood.48–50 Whether GDNF only affects neurons in the CNS has not yet been resolved.
Drug therapy
Published in Jeremy Playfer, John Hindle, Andrew Lees, Parkinson's Disease in the Older Patient, 2018
Beyond neuroprotection, neuro-rescue with the regeneration of dying neurones is a possibility, particularly with the use of nerve growth factors such as glial cell line-derived neurotrophic factor (GDNF).84 More radical neuro-restoration will depend on techniques of cell biology, including gene therapy and surgical cell implantation of stem cells or nerve growth factors. These fall outside the remit of this chapter.
MicroRNA machinery in Parkinson’s disease: a platform for neurodegenerative diseases
Published in Expert Review of Neurotherapeutics, 2022
Glial cell line-derived neurotrophic factor (GDNF) is recognized as the potential promoter of survival/differentiation of dopaminergic neurons in embryonic midbrain cultures.[102,103] It is, thus, considered as an important target in therapeutic architectures of PD. Treatment of injured MN9D cells with GDNF, which sounds very promising in the improvement of main PD-related functional deficits,[104,105] led to alter significantly the expression of >100 miRNAs.[106] When looking at altered miRNAs following GDNF treatment for 30 min, 1 h and 3 h, a simple but interesting bias existed in increasing the number of upregulated miRNAs (30 min: 7; 1 h: 31; and 3 h: 70), and also inversely, in decreasing the number of downregulated miRNAs (30 min: 20; 1 h: 15; and 3 h: 0) over the treatment time.[106] This investigation eventually established a set consisted of target genes of miRNAs, which were altered under the impression of GDNF treatment, and as expected, these genes were divided into two, downregulated genes, for examples, Dapp1 (miR-761, miR-691 and miR-697), Rassf4 (miR-695, miR-761, miR-691, miR-342-5p and miR-697), Gtpbp2 (miR-695, miR-761 and miR-691) and Shc3 (miR-691), and upregulated genes, for examples, Gse1 (miR-188-5p, miR-532-5p), Traf3 (miR-188-5p, miR-532-5p) and Bclaf1 (miR-188-5p).[106]
Innovations and revolutions in reducing retinal ganglion cell loss in glaucoma
Published in Expert Review of Ophthalmology, 2021
Mary Kelada, Daniel Hill, Timothy E. Yap, Haider Manzar, M. Francesca Cordeiro
Recent pre-clinical models have demonstrated that glial cell line-derived neurotrophic factor (GDNF) could act synergistically with CNTF to confer increased neuroprotection to RGCs than either factor alone [93]. The intravitreal transplantation of GDNF-expressing neuronal stem (NS) cell lines 1 day after RGC axotomy in murine models increased the survival of RGCs by 3.8 times, compared to control retinas. Similarly, the intravitreal transplantation of CNTF-expressing NS 1 day after axotomy of RGCs in adult mice resulted in 3.7-fold more RGCs than in control retinas. However, when GDNF- and CNTF-expressing NS were co-administered, RGC survival was dramatically increased, with 14.3-fold more RGCs than control retinas 8 weeks after injury compared to control retinas [93]. Although yet to progress to clinical trials, the combination of neurotrophic factors could represent a novel neuroprotective strategy in glaucoma. However, this strategy may also be limited by issues of bioavailability.
Novel therapeutic targets for amyotrophic lateral sclerosis: ribonucleoproteins and cellular autonomy
Published in Expert Opinion on Therapeutic Targets, 2020
Cellular implantation is an alternative potential therapeutic consideration (Figure 3). Harnessing astrocytes as cellular material currently seems tractable as this bypasses the challenge of neuronal implantation (i.e. reconstructing highly complex connections over long distances between motor neurons and their distal muscle targets). Multiple clinical trials of cell transplantation have used neural progenitor cells to generate astrocytes and interneurons, which can release growth factors and/or reduce inflammation to protect surrounding motor neurons [140–143]. Another study utilized human neural progenitor cells that had been genetically engineered ex vivo to produce glial cell line-derived neurotrophic factor (GDNF), a protein that promotes the survival of neurons and has proved beneficial in ALS rat models [144,145]. Transplantation of the GDNF-secreting cells into the spinal cord of ALS patients is now in phase I/IIa clinical trials (NCT02943850). Another FDA-approved cell transplantation trial using highly purified glial-restricted progenitors is also planned [146]. Notably, grafting human iPSCs-derived neural progenitor cells leads to astrocyte differentiation and improvement in the lifespan of rodents [147,148], underlining the utility of this source of cellular material for transplantation in ALS therapy. Cumulatively, astrocytes represent an underexplored therapeutic opportunity in ALS but it remains possible that different phases of disease may necessitate distinct therapeutic approaches.