Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors

Nishijima, Euido; Honda, Sari; Kitamura, Yuta; Namekata, Kazuhiko; Kimura, Atsuko; Guo, Xiaoli; Azuchi, Yuriko; Harada, Chikako; Murakami, Akira; Matsuda, Akira; Nakano, Tadashi; Parada, Luis F.; Harada, Takayuki

doi:10.1016/j.ymthe.2022.11.018

Cited by 13 publications

(3 citation statements)

References 55 publications

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“…Recently, intraocular injection of anti-VEGF agents to prevent neovascularization is usual worldwide for the treatment of diabetic retinopathy, age-related macular degeneration, etc. On the other hand, we recently developed a AAV vector which can prevent the progress of neurodegeneration in mouse models of glaucoma [ 35 ]. However, gene therapy is not yet common and there are many restrictions for routine medical care.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection and axon regeneration by novel low-molecular-weight compounds through the modification of DOCK3 conformation

et al. 2023

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Dedicator of cytokinesis 3 (DOCK3) is an atypical member of the guanine nucleotide exchange factors (GEFs) and plays important roles in neurite outgrowth. DOCK3 forms a complex with Engulfment and cell motility protein 1 (Elmo1) and effectively activates Rac1 and actin dynamics. In this study, we screened 462,169 low-molecular-weight compounds and identified the hit compounds that stimulate the interaction between DOCK3 and Elmo1, and neurite outgrowth in vitro. Some of the derivatives from the hit compound stimulated neuroprotection and axon regeneration in a mouse model of optic nerve injury. Our findings suggest that the low-molecular-weight DOCK3 activators could be a potential therapeutic candidate for treating axonal injury and neurodegenerative diseases including glaucoma.

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Section: Discussionmentioning

confidence: 99%

Neuroprotection and axon regeneration by novel low-molecular-weight compounds through the modification of DOCK3 conformation

et al. 2023

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“…The sustained expression of BDNF in Müller cells has been demonstrated to confer protection upon RGCs following optic nerve injury ( 58 , 59 ). Recent research has spotlighted the adeno-associated virus (AAV)-mediated enhancement of TrkB signaling in RGCs, leading to both cryoprotection against glaucoma and a vigorous resurgence of RGC axons ( 60 ) ( Figure 2D ). Collectively, these findings posit that Müller cell-derived neurotrophic factors, with particular emphasis on BDNF, hold paramount importance in protecting RGCs against glaucoma.…”

Section: The Role Of Müller Cells In the Protection Of Rgcsmentioning

confidence: 99%

Glial cells as a promising therapeutic target of glaucoma: beyond the IOP

Shinozaki,

Namekata,

Guo

et al. 2024

Front. Ophthalmol.

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Glial cells, a type of non-neuronal cell found in the central nervous system (CNS), play a critical role in maintaining homeostasis and regulating CNS functions. Recent advancements in technology have paved the way for new therapeutic strategies in the fight against glaucoma. While intraocular pressure (IOP) is the most well-known modifiable risk factor, a significant number of glaucoma patients have normal IOP levels. Because glaucoma is a complex, multifactorial disease influenced by various factors that contribute to its onset and progression, it is imperative that we consider factors beyond IOP to effectively prevent or slow down the disease’s advancement. In the realm of CNS neurodegenerative diseases, glial cells have emerged as key players due to their pivotal roles in initiating and hastening disease progression. The inhibition of dysregulated glial function holds the potential to protect neurons and restore brain function. Consequently, glial cells represent an enticing therapeutic candidate for glaucoma, even though the majority of glaucoma research has historically concentrated solely on retinal ganglion cells (RGCs). In addition to the neuroprotection of RGCs, the proper regulation of glial cell function can also facilitate structural and functional recovery in the retina. In this review, we offer an overview of recent advancements in understanding the non-cell-autonomous mechanisms underlying the pathogenesis of glaucoma. Furthermore, state-of-the-art technologies have opened up possibilities for regenerating the optic nerve, which was previously believed to be incapable of regeneration. We will also delve into the potential roles of glial cells in the regeneration of the optic nerve and the restoration of visual function.

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“…Gene therapy offers an avenue for sustained production of neurotrophins that would otherwise have a transient effect given their short half-lives and sensitivity to degradation en route to the retina [7]. Many studies have successfully demonstrated RGC protection in animal glaucoma models using viral vectors to locally express brain-derived neurotrophic factor (BDNF) and its TrkB receptor [21–25,26 ▪ ], ciliary neurotrophic factor (CNTF) [27–29], and glial cell derived neurotrophic factor (GDNF) [30].…”

Section: Gene Therapymentioning

confidence: 99%

Future directions of glaucoma treatment: emerging gene, neuroprotection, nanomedicine, stem cell, and vascular therapies

Ciociola,

Fernandez,

Kaufmann

et al. 2023

Current Opinion in Ophthalmology

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Purpose of review The aim of this article is to summarize current research on novel gene, stem cell, neuroprotective, nanomedicine, and vascular therapies for glaucoma. Recent findings Gene therapy using viral vectors and siRNA have been shown to reduce intraocular pressure by altering outflow and production of aqueous humor, to reduce postsurgical fibrosis with few adverse effects, and to increase retinal ganglion cell (RGC) survival in animal studies. Stem cells may treat glaucoma by replacing or stimulating proliferation of trabecular meshwork cells, thus restoring outflow facility. Stem cells can also serve a neuroprotective effect by differentiating into RGCs or preventing RGC loss via secretion of growth factors. Other developing neuroprotective glaucoma treatments which can prevent RGC death include nicotinamide, the NT-501 implant which secretes ciliary neurotrophic factor, and a Fas-L inhibitor which are now being tested in clinical trials. Recent studies on vascular therapy for glaucoma have focused on the ability of Rho Kinase inhibitors and dronabinol to increase ocular blood flow. Summary Many novel stem cell, gene, neuroprotective, nanomedicine, and vascular therapies have shown promise in preclinical studies, but further clinical trials are needed to demonstrate safety and efficacy in human glaucomatous eyes. Although likely many years off, future glaucoma therapy may take a multifaceted approach.

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Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors

Cited by 13 publications

References 55 publications

Neuroprotection and axon regeneration by novel low-molecular-weight compounds through the modification of DOCK3 conformation

Neuroprotection and axon regeneration by novel low-molecular-weight compounds through the modification of DOCK3 conformation

Glial cells as a promising therapeutic target of glaucoma: beyond the IOP

Future directions of glaucoma treatment: emerging gene, neuroprotection, nanomedicine, stem cell, and vascular therapies

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