Gene therapy for optic nerve disease

Martin, Keith R; Quigley, Harry A.

doi:10.1038/sj.eye.6701579

Cited by 46 publications

(26 citation statements)

References 43 publications

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“…The optic nerve (ON) represents a unique model system for the study of axonal pathology in the CNS because of its accessibility and the possibility to manipulate the system via transfection of retinal ganglion cells (RGC) (13)(14)(15). Moreover, dysfunction of ON axons has clinical relevance for the pathogenesis of optic neuritis, glaucoma, Leber's optic atrophy, and trauma (16)(17)(18).…”

mentioning

confidence: 99%

Mechanisms of acute axonal degeneration in the optic nerve in vivo

Knöferle

Koch²,

Ostendorf³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

266

215

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Axonal degeneration is an initial key step in traumatic and neurodegenerative CNS disorders. We established a unique in vivo epifluorescence imaging paradigm to characterize very early events in axonal degeneration in the rat optic nerve. Single retinal ganglion cell axons were visualized by AAV-mediated expression of dsRed and this allowed the quantification of postlesional acute axonal degeneration (AAD). EM analysis revealed severe structural alterations of the cytoskeleton, cytoplasmatic vacuolization, and the appearance of autophagosomes within the first hours after lesion. Inhibition of autophagy resulted in an attenuation of acute axonal degeneration. Furthermore, a rapid increase of intraaxonal calcium levels following crush lesion could be visualized using a calciumsensitive dye. Application of calcium channel inhibitors prevented crush-induced calcium increase and markedly attenuated axonal degeneration, whereas application of a calcium ionophore aggravated the degenerative phenotype. We finally demonstrate that increased postlesional autophagy is calcium dependent and thus mechanistically link autophagy and intraaxonal calcium levels. Both processes are proposed to be major targets for the manipulation of axonal degeneration in future therapeutic settings.CNS trauma | live imaging | calcium influx | autophagy A xonal degeneration plays a pivotal role in the pathogenesis of numerous neurological disorders frequently preceding neuronal cell death and resulting in persistent functional disability. Traumatic spinal cord or peripheral nerve injury represent classical conditions where mechanical disruption of axonal integrity results in nervous system dysfunction (1, 2). Several degenerative CNS diseases show prominent axonal pathology already early in the disease course, such as the degeneration of nigrostriatal projection tracts or cardiac sympathetic nerves in Parkinson's disease (3) or corticospinal tracts in amyotrophic lateral sclerosis (4). Key features of axonal degeneration seem to be similar despite variable etiology. The distal part of the lesioned axon undergoes Wallerian degeneration (WD) characterized by initial axonal stability followed by rapid degeneration, fragmentation, and blebbing of the remaining axon, microtubule disassembly, and phagocytic clearance of the lesion site. The proximal part was reported to remain more stable than its distal counterpart (5-8), but imaging of the spinal cord in vivo visualized mechanisms of acute axonal degeneration (AAD) within the first minutes after lesion. In contrast to WD, AAD results in sudden axonal disintegration and extended for ≈300 μm proximal and distal to the lesion (9). One of the putative initiating steps in axonal degeneration is the influx of extracellular calcium, which is suggested to destabilize the axon and to transmit apoptotic signals to the neuronal soma (10-12).The optic nerve (ON) represents a unique model system for the study of axonal pathology in the CNS because of its accessibility and the possibility to manipulate the system...

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mentioning

confidence: 99%

Mechanisms of acute axonal degeneration in the optic nerve in vivo

Knöferle

Koch²,

Ostendorf³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

266

215

View full text Add to dashboard Cite

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“…Following a single intravitreal injection of AAV, a highly effi cient transduction of RGCs was achieved in a rat model of glaucoma. In this model it was found that AAVmediated gene therapy with BDNF has a signifi cant neuroprotective effect compared to saline or control virus injections (Martin and Quigley, 2004). BDNF receptor TrkB is markedly downregulated after axotomy of the optic nerve.…”

Section: Neurotrophic Factorsmentioning

confidence: 98%

Progress and Prospects in Ocular Gene Therapy

Liu¹,

Rasmussen²,

Bennett³

et al. 2008

Ocular Therapeutics

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“…Gene therapy has also been explored as a potential therapy for red-green colour blindness,73 corneal neovascularisation,74 a variety of other corneal diseases, including allograft rejection, postexcimer laser scarring and herpes simplex keratitis,93 uveal melanoma94 and optic nerve diseases, including optic nerve trauma, optic neuritis and Leber's hereditary optic neuropathy 95…”

Section: Ocular Gene Therapy In Experimental Modelsmentioning

confidence: 99%

Gene therapy for ocular diseases

Liu

Tuo

Chan

2010

British Journal of Ophthalmology

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The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

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Gene therapy for optic nerve disease

Cited by 46 publications

References 43 publications

Mechanisms of acute axonal degeneration in the optic nerve in vivo

Mechanisms of acute axonal degeneration in the optic nerve in vivo

Progress and Prospects in Ocular Gene Therapy

Gene therapy for ocular diseases

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