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A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration.

ABSTRACT: Retinal degenerations are a large cluster of diseases characterized by the irreversible loss of light-sensitive photoreceptors that impairs the vision of 9.1 million people in the US. An attractive treatment option is to use gene therapy to deliver broad-spectrum neuroprotective factors. However, this approach has had limited clinical translation because of the inability to control transgene expression. To address this problem, we generated an adeno-associated virus vector named RPF2 that was engineered to express domains of leukemia inhibitory factor fused to the destabilization domain of bacterial dihydrofolate reductase. Fusion proteins containing the destabilization domain are degraded in mammalian cells but can be stabilized with the binding of the drug trimethoprim. Our data show that expression levels of RPF2 are tightly regulated by the dose of trimethoprim and can be reversed by trimethoprim withdrawal. We further show that stabilized RPF2 can protect photoreceptors and prevent blindness in treated mice.

SUBMITTER: Santiago CP

PROVIDER: S-EPMC6171322 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration.

Santiago Clayton P CP Keuthan Casey J CJ Boye Sanford L SL Boye Shannon E SE Imam Aisha A AA Ash John D JD

Molecular therapy : the journal of the American Society of Gene Therapy 20180719 10

Retinal degenerations are a large cluster of diseases characterized by the irreversible loss of light-sensitive photoreceptors that impairs the vision of 9.1 million people in the US. An attractive treatment option is to use gene therapy to deliver broad-spectrum neuroprotective factors. However, this approach has had limited clinical translation because of the inability to control transgene expression. To address this problem, we generated an adeno-associated virus vector named RPF2 that was en ...[more]

PMID: 30078764

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Project description:Despite to outbreaks of highly pathogenic beta and alpha coronaviruses including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and human coronavirus, the newly emerged 2019 coronavirus (COVID-19) is considered as a lethal zoonotic virus due to its deadly respiratory syndrome and high mortality rate among the human. Globally, more than 3,517,345 cases have been confirmed with 243,401 deaths due to Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19. The antiviral drug discovery activity is required to control the persistence of COVID-19 circulation and the potential of the future emergence of coronavirus. However, the present review aims to highlight the important antiviral approaches, including interferons, ribavirin, mycophenolic acids, ritonavir, lopinavir, inhibitors, and monoclonal antibodies (mAbs) to provoke the nonstructural proteins and deactivate the structural and essential host elements of the virus to control and treat the infection of COVID-19 by inhibiting the viral entry, viral RNA replication and suppressing the viral protein expression. Moreover, the present review investigates the epidemiology, diagnosis, structure, and replication of COVID-19 for better understanding. It is recommended that these proteases, inhibitors, and antibodies could be a good therapeutic option in drug discovery to control the newly emerged coronavirus.HighlightsCOVID-19 has more than 79.5% identical sequence to SARS-CoV and a 96% identical sequence of the whole genome of bat coronaviruses.Acute respiratory distress syndrome (ARDS), renal failure, and septic shock are the possible clinical symptoms associated with COVID-19.Different antivirals, including interferons, ribavirin, lopinavir, and monoclonal antibodies (mAbs) could be the potent therapeutic agents against COVID-19.The initial clinical trials on hydroquinone in combination with azithromycin showed an admirable result in the reduction of COVID-19.The overexpression of inflammation response, cytokine dysregulation, and induction of apoptosis could be an well-organized factors to reduce the pathogenicity of COVID-19.

Dataset Information

A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration.

Publications

A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration.

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