Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Beltran, William A.; Cideciyan, Artur V.; Lewin, Alfred S.; Hauswirth, William W.; Jacobson, Samuel G.; Aguirre, Gustavo D.

doi:10.1101/cshperspect.a017392

Cited by 21 publications

(34 citation statements)

References 83 publications

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“…It is possible that other proteins (e.g., GC and carbonic anhydrase C) would respond differently as they are known to decrease in experimental retinal detachment in adult cats (Lewis et al, 1994). Therapeutic approaches in RP and other hereditary diseases involving retinal degeneration might aim to restore the gene defect by gene-replacement (Beltran et al, 2014) or stem-cell transplantation (He et al, 2014). Retinal degeneration might also be palliated or slowed by controlling the neuroinflammatory framework.…”

Section: Retinitis Pigmentosa (Rp)mentioning

confidence: 97%

Glia–neuron interactions in the mammalian retina

Vecino

Rodríguez

Ruzafa

et al. 2016

Progress in Retinal and Eye Research

615

533

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The mammalian retina provides an excellent opportunity to study glia-neuron interactions and the interactions of glia with blood vessels. Three main types of glial cells are found in the mammalian retina that serve to maintain retinal homeostasis: astrocytes, Müller cells and resident microglia. Müller cells, astrocytes and microglia not only provide structural support but they are also involved in metabolism, the phagocytosis of neuronal debris, the release of certain transmitters and trophic factors and K(+) uptake. Astrocytes are mostly located in the nerve fibre layer and they accompany the blood vessels in the inner nuclear layer. Indeed, like Müller cells, astrocytic processes cover the blood vessels forming the retinal blood barrier and they fulfil a significant role in ion homeostasis. Among other activities, microglia can be stimulated to fulfil a macrophage function, as well as to interact with other glial cells and neurons by secreting growth factors. This review summarizes the main functional relationships between retinal glial cells and neurons, presenting a general picture of the retina recently modified based on experimental observations. The preferential involvement of the distinct glia cells in terms of the activity in the retina is discussed, for example, while Müller cells may serve as progenitors of retinal neurons, astrocytes and microglia are responsible for synaptic pruning. Since different types of glia participate together in certain activities in the retina, it is imperative to explore the order of redundancy and to explore the heterogeneity among these cells. Recent studies revealed the association of glia cell heterogeneity with specific functions. Finally, the neuroprotective effects of glia on photoreceptors and ganglion cells under normal and adverse conditions will also be explored.

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Section: Retinitis Pigmentosa (Rp)mentioning

confidence: 97%

Glia–neuron interactions in the mammalian retina

Vecino

Rodríguez

Ruzafa

et al. 2016

Progress in Retinal and Eye Research

615

533

View full text Add to dashboard Cite

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“…There are several mouse models of RPGR X-linked RP and two canine models, with the canine models recapitulating distinct RPGR X-linked RP phenotypes (107)(108)(109)(110). Subretinal injection of a AAV2/5 vector carrying human RPGR to the XLRPA2 canine model, which harbors a microdeletion in canine RPGR ORF15, showed preserved photoreceptor nuclei in treated regions and correction of opsin protein translocation (111). Currently, there are two phase I/II trials examining the efficacy and safety of AAV2/5 vector delivery of a native RPGR gene to affected individuals (see Table 1).…”

Section: Inner Retinal Disordersmentioning

confidence: 99%

Gene therapy and genome surgery in the retina

DiCarlo¹,

Mahajan²,

Tsang³

2018

Journal of Clinical Investigation

113

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Precision medicine seeks to treat disease with molecular specificity. Advances in genome sequence analysis, gene delivery, and genome surgery have allowed clinician-scientists to treat genetic conditions at the level of their pathology. As a result, progress in treating retinal disease using genetic tools has advanced tremendously over the past several decades. Breakthroughs in gene delivery vectors, both viral and nonviral, have allowed the delivery of genetic payloads in preclinical models of retinal disorders and have paved the way for numerous successful clinical trials. Moreover, the adaptation of CRISPR-Cas systems for genome engineering have enabled the correction of both recessive and dominant pathogenic alleles, expanding the disease-modifying power of gene therapies. Here, we highlight the translational progress of gene therapy and genome editing of several retinal disorders, including RPE65-, CEP290-, and GUY2D-associated Leber congenital amaurosis, as well as choroideremia, achromatopsia, Mer tyrosine kinase- (MERTK-) and RPGR X-linked retinitis pigmentosa, Usher syndrome, neovascular age-related macular degeneration, X-linked retinoschisis, Stargardt disease, and Leber hereditary optic neuropathy.

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“…Lastly, a common X-linked form of RP (XLRP) is caused by mutation to the RP GTPase regulator (RPGR) gene. No treatment is available to date, but in two canine models rAAV2/5-mediated expression of RPGR in rods and cones rescues photoreceptor blindness and prevents disease onset at an early age 87 .…”

Section: Rare Disease and Current Raav Pre-clinical And Clinical Smentioning

confidence: 99%

Recombinant adeno-associated virus vectors in the treatment of rare diseases

Hastie

Samulski

2015

Expert Opinion on Orphan Drugs

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Introduction An estimated 25 million Americans are living with rare diseases. Adeno-associated virus (AAV)-mediated gene therapy is an emerging therapeutic option for the more than 7,000 identified rare diseases. This paper highlights the benefits of AAV therapy compared to conventional small molecules, discusses current pre-clinical and clinical applications of AAV-mediated gene therapy, and offers insights into cutting edge research that will shape the future of AAV for broad therapeutic use. Areas covered In this review the biology of AAV and our ability to generate disease-specific variants is summarized. Limitations of current therapy are reviewed, with an emphasis on immune detection of virus, viral tropism and tissue targeting, and limitations of gene expression. Information for this review was found using PubMed and clinicaltrials.gov. Expert opinion Currently the scope of clinical trials of AAV gene therapy is concentrated in an array of phase I/II safety trials with less than two dozen rare diseases featured. Pre-clinical, translational studies are expanding in number as developments within the last decade have made generation of improved AAV vectors available to more researchers. Further, one bottleneck that is being overcome is the availability of disease models, which will allow for improved preclinical testing and advancement of AAV to more clinical applications.

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Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Cited by 21 publications

References 83 publications

Glia–neuron interactions in the mammalian retina

Glia–neuron interactions in the mammalian retina

Gene therapy and genome surgery in the retina

Recombinant adeno-associated virus vectors in the treatment of rare diseases

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