scholarly journals Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction

2020 ◽  
Vol 14 ◽  
Author(s):  
Daniel M. Maloney ◽  
Naomi Chadderton ◽  
Sophia Millington-Ward ◽  
Arpad Palfi ◽  
Ciara Shortall ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Optic Atrophy ◽  
Therapeutic Interventions ◽  
Fibroblast Cells ◽  
Retinal Ganglion ◽  
Cell Degeneration

Optic Atrophy 1 (OPA1) is a mitochondrially targeted GTPase that plays a pivotal role in mitochondrial health, with mutations causing severe mitochondrial dysfunction and typically associated with Dominant Optic Atrophy (DOA), a progressive blinding disease involving retinal ganglion cell loss and optic nerve damage. In the current study, we investigate the use of codon-optimized versions of OPA1 isoform 1 and 7 as potential therapeutic interventions in a range of in vitro and in vivo models of mitochondrial dysfunction. We demonstrate that both isoforms perform equally well in ameliorating mitochondrial dysfunction in OPA1 knockout mouse embryonic fibroblast cells but that OPA1 expression levels require tight regulation for optimal benefit. Of note, we demonstrate for the first time that both OPA1 isoform 1 and 7 can be used independently to protect spatial visual function in a murine model of retinal ganglion cell degeneration caused by mitochondrial dysfunction, as well as providing benefit to mitochondrial bioenergetics in DOA patient derived fibroblast cells. These results highlight the potential value of OPA1-based gene therapy interventions.

scholarly journals Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Myoung Sup Shim ◽  
Yuji Takihara ◽  
Keun-Young Kim ◽  
Takeshi Iwata ◽  
Beatrice Y. J. T. Yue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Open Angle Glaucoma ◽  
Mitochondrial Fission ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Transport Dynamics

Abstract Mutations in optineurin (OPTN) are linked to the pathology of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis. Emerging evidence indicates that OPTN mutation is involved in accumulation of damaged mitochondria and defective mitophagy. Nevertheless, the role played by an OPTN E50K mutation in the pathogenic mitochondrial mechanism that underlies retinal ganglion cell (RGC) degeneration in POAG remains unknown. We show here that E50K expression induces mitochondrial fission-mediated mitochondrial degradation and mitophagy in the axons of the glial lamina of aged E50K−tg mice in vivo. While E50K activates the Bax pathway and oxidative stress, and triggers dynamics alteration-mediated mitochondrial degradation and mitophagy in RGC somas in vitro, it does not affect transport dynamics and fission of mitochondria in RGC axons in vitro. These results strongly suggest that E50K is associated with mitochondrial dysfunction in RGC degeneration in synergy with environmental factors such as aging and/or oxidative stress.

scholarly journals Exosome-Mediated Delivery of the Neuroprotective Peptide PACAP38 Promotes Retinal Ganglion Cell Survival and Axon Regeneration in Rats With Traumatic Optic Neuropathy

2021 ◽  
Vol 9 ◽  
Author(s):  
Tian Wang ◽  
Yiming Li ◽  
Miao Guo ◽  
Xue Dong ◽  
Mengyu Liao ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Optic Neuropathy ◽  
Axon Regeneration ◽  
Retinal Ganglion ◽  
Traumatic Optic Neuropathy ◽  
Fiber Layer

Traumatic optic neuropathy (TON) refers to optic nerve damage caused by trauma, leading to partial or complete loss of vision. The primary treatment options, such as hormonal therapy and surgery, have limited efficacy. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), a functional endogenous neuroprotective peptide, has emerged as a promising therapeutic agent. In this study, we used rat retinal ganglion cell (RGC) exosomes as nanosized vesicles for the delivery of PACAP38 loaded via the exosomal anchor peptide CP05 (EXOPACAP38). EXOPACAP38 showed greater uptake efficiency in vitro and in vivo than PACAP38. The results showed that EXOPACAP38 significantly enhanced the RGC survival rate and retinal nerve fiber layer thickness in a rat TON model. Moreover, EXOPACAP38 significantly promoted axon regeneration and optic nerve function after injury. These findings indicate that EXOPACAP38 can be used as a treatment option and may have therapeutic implications for patients with TON.

Neuroprotective effects of minocycline against in vitro and in vivo retinal ganglion cell damage

2005 ◽  
Vol 1053 (1-2) ◽  
pp. 185-194 ◽  
Author(s):  
Masamitsu Shimazawa ◽  
Tetsumori Yamashima ◽  
Neeraj Agarwal ◽  
Hideaki Hara
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Cell Damage ◽  
Retinal Ganglion ◽  
Neuroprotective Effects

scholarly journals Progressive optic atrophy in a retinal ganglion cell-specific mouse model of complex I deficiency

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Luyu Wang ◽  
Mikael Klingeborn ◽  
Amanda M. Travis ◽  
Ying Hao ◽  
Vadim Y. Arshavsky ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Optic Atrophy ◽  
Complex I ◽  
Time Course ◽  
Retinal Cell ◽  
Preclinical Model ◽  
Retinal Ganglion ◽  
Mouse Line

Abstract Optic atrophy resulting from retinal ganglion cell (RGC) degeneration is a prominent ocular manifestation of mitochondrial dysfunction. Although transgenic mice lacking the mitochondrial complex I accessory subunit NDUFS4 develop early-onset optic atrophy, severe systemic mitochondrial dysfunction leads to very early death and makes this mouse line impractical for studying the pathobiology of mitochondrial optic neuropathies. Theoretically, RGC-specific inactivation of ndufs4 would allow characterization of RGC degeneration over a longer time course, provided that RGC death from mitochondrial dysfunction is a cell-autonomous process. We demonstrate that the vesicular glutamate transporter VGLUT2 may be exploited to drive robust Cre recombinase expression in RGCs without any expression observed in directly neighboring retinal cell types. Deletion of ndufs4 in RGCs resulted in reduced expression of NDUFS4 protein within the optic nerves of Vglut2-Cre;ndufs4loxP/loxP mice. RGC degeneration in Vglut2-Cre;ndufs4loxP/loxP retinas commenced around postnatal day 45 (P45) and progressed to loss of two-thirds of RGCs by P90, confirming that intrinsic complex I dysfunction is sufficient to induce RGC death. The rapidly-developing optic atrophy makes the Vglut2-Cre;ndufs4loxP/loxP mouse line a promising preclinical model for testing therapies for currently untreatable mitochondrial optic neuropathies such as Leber Hereditary Optic Neuropathy.

scholarly journals Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 581
Author(s):  
Jess Rhee ◽  
Kendrick Co Shih
Keyword(s):  
Gene Therapy ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
English Language ◽  
Regulation Of Gene Expression ◽  
Retinal Ganglion ◽  
Aav Vector ◽  
Messenger Ribonucleic Acid

We systematically reviewed published translational research on gene-based therapy for retinal ganglion cell (RGC) neuroprotection. A search was conducted on Entrez PubMed on 23 December 2020 using the keywords “gene therapy”, “retinal ganglion cell” and “neuroprotection”. The initial search yielded 82 relevant articles. After restricting publications to those with full text available and in the English language, and then curating for only original articles on gene-based therapy, the final yield was 18 relevant articles. From the 18 papers, 17 of the papers utilized an adeno-associated viral (AAV) vector for gene therapy encoding specific genes of interest. Specifically, six of the studies utilized an AAV vector encoding brain-derived neurotrophic factor (BDNF), two of the studies utilized an AAV vector encoding erythropoietin (EPO), the remaining 10 papers utilized AAV vectors encoding different genes and one microRNA study. Although the literature shows promising results in both in vivo and in vitro models, there is still a significant way to go before gene-based therapy for RGC neuroprotection can proceed to clinical trials. Namely, the models of injury in many of the studies were more acute in nature, unlike the more progressive and neurodegenerative pathophysiology of diseases, such as glaucoma. The regulation of gene expression is also highly unexplored despite the use of AAV vectors in the majority of the studies reviewed. It is also expected that with the successful launch of messenger ribonucleic acid (mRNA)-based vaccinations in 2020, we will see a shift towards this technology for gene-based therapy in glaucoma neuroprotection.

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