July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Restoring miRNAs of the miR-183/96/182 cluster results in target gene regulation and ameliorates symptoms of retinal degeneration in a mouse model of retinitis pigmentosa
Author Affiliations & Notes
  • melanie Hermreck
    R&D, miRagen Therapeutics Inc, Boulder, Colorado, United States
  • Anita Seto
    R&D, miRagen Therapeutics Inc, Boulder, Colorado, United States
  • Katherine Hutnik
    R&D, miRagen Therapeutics Inc, Boulder, Colorado, United States
  • Aimee Jackson
    R&D, miRagen Therapeutics Inc, Boulder, Colorado, United States
  • Footnotes
    Commercial Relationships   melanie Hermreck, None; Anita Seto, None; Katherine Hutnik, None; Aimee Jackson, WO 2016/149370 (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4969. doi:
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      melanie Hermreck, Anita Seto, Katherine Hutnik, Aimee Jackson; Restoring miRNAs of the miR-183/96/182 cluster results in target gene regulation and ameliorates symptoms of retinal degeneration in a mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4969.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinitis pigmentosa (RP) is an inherited disease, characterized by gradual loss of photoreceptors in the retina, which results in progressive “tunnel vision” and eventual blindness. Few to no therapies are currently available to treat or prevent the vision loss associated with RP. The miR-183/96/182 cluster includes microRNAs that function in development and maintenance of sensory neurons, including photoreceptors. Knockout of the miR-183/96/182 cluster in mice recapitulates features of retinitis pigmentosa, including the loss of photoreceptors, and expression of the microRNAs is sufficient for formation of outer segments, validating the role for these microRNAs in photoreceptor maintenance and function. This study investigated the impact of synthetic mimics of the miR-183 cluster on photoreceptor function and visual acuity.

Methods : Synthetic mimics corresponding to the microRNAs in the cluster were delivered passively to primary rat and human retinal cells, and were evaluated for their ability to regulate known target genes involved in the photo-transduction pathway. Efficacy was evaluated in vivo using a mouse model of light-induced retinal degeneration. rd10 mice were treated with a single intravitreal injection consisting of a pool of synthetic mimics for the 3 microRNAs in the miR-183/96/182 cluster. Photoreceptor function, visual acuity, and degeneration of photoreceptors in the outer nuclear layer were assessed over time.

Results : Synthetic mimics demonstrated functional uptake in primary rat and human retinal cell cultures as measured by regulation of target genes within the photo-transduction pathway. Administration of mimics in vivo improved photoreceptor function and visual acuity compared to vehicle treated animals.

Conclusions : The miR-183/96/182 cluster plays a fundamental role in establishment and maintenance of photoreceptors and the data described herein demonstrate that restoring miRNA function results in target engagement and improved photoreceptor function. Thus, administration of mimics corresponding to one or more of the microRNAs in the miR-183 cluster could represent a novel therapeutic approach to delay or prevent photoreceptor loss in patients with retinitis pigmentosa.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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