Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy

Anil Chekuri, Bhubanananda Sahu, Venkata Ramana Murthy Chavali, Marina Voronchikhina, Angel Soto-Hermida, John J. Suk, Akhila N. Alapati, Dirk Uwe Bartsch, Raul Ayala-Ramirez, Juan C. Zenteno, Astra Dinculescu, Monica Jablonski, Shyamanga Borooah, Radha Ayyagari

Research output: Contribution to journalArticle

Abstract

Patients harboring homozygous c.498-499insC mutations in MFRP demonstrate hyperopia, microphthalmia, retinitis pigmentosa, retinal pigment epithelial atrophy, variable degrees of foveal edema, and optic disc drusen. The disease phenotype is variable, however, with some patients maintaining good central vision and cone function till late in the disease. A knock-in mouse model with the c.498-499insC mutation in Mfrp (Mfrp KI/KI) was developed to understand the effects of these mutations in the retina. The model shares many of the features of human clinical disease, including reduced axial length, hyperopia, retinal degeneration, retinal pigment epithelial atrophy, and decreased electrophysiological responses. In addition, the eyes of these mice had a significantly greater refractive error (p < 0.01) when compared to age-matched wild-type control animals. Administration of recombinant adeno-associated virus-mediated Mfrp gene therapy significantly prevented thinning from retinal neurodegeneration (p < 0.005) and preserved retinal electrophysiology (p < 0.001) when treated eyes were compared to contralateral sham-treated control eyes. The Mfrp KI/KI mice will serve as a useful tool to model human disease and point to a potential gene therapeutic approach for patients with preserved vision and electrophysiological responses in MFRP-related retinopathy.

Original languageEnglish (US)
Pages (from-to)632-650
Number of pages19
JournalHuman Gene Therapy
Volume30
Issue number5
DOIs
StatePublished - May 1 2019

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Genetic Therapy
Hyperopia
Retinal Pigments
Mutation
Atrophy
Optic Disk Drusen
Microphthalmos
Dependovirus
Retinal Degeneration
Papilledema
Wild Animals
Retinitis Pigmentosa
Refractive Errors
Electrophysiology
Retina
Phenotype
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Chekuri, A., Sahu, B., Chavali, V. R. M., Voronchikhina, M., Soto-Hermida, A., Suk, J. J., ... Ayyagari, R. (2019). Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy. Human Gene Therapy, 30(5), 632-650. https://doi.org/10.1089/hum.2018.192

Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy. / Chekuri, Anil; Sahu, Bhubanananda; Chavali, Venkata Ramana Murthy; Voronchikhina, Marina; Soto-Hermida, Angel; Suk, John J.; Alapati, Akhila N.; Bartsch, Dirk Uwe; Ayala-Ramirez, Raul; Zenteno, Juan C.; Dinculescu, Astra; Jablonski, Monica; Borooah, Shyamanga; Ayyagari, Radha.

In: Human Gene Therapy, Vol. 30, No. 5, 01.05.2019, p. 632-650.

Research output: Contribution to journalArticle

Chekuri, A, Sahu, B, Chavali, VRM, Voronchikhina, M, Soto-Hermida, A, Suk, JJ, Alapati, AN, Bartsch, DU, Ayala-Ramirez, R, Zenteno, JC, Dinculescu, A, Jablonski, M, Borooah, S & Ayyagari, R 2019, 'Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy', Human Gene Therapy, vol. 30, no. 5, pp. 632-650. https://doi.org/10.1089/hum.2018.192
Chekuri A, Sahu B, Chavali VRM, Voronchikhina M, Soto-Hermida A, Suk JJ et al. Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy. Human Gene Therapy. 2019 May 1;30(5):632-650. https://doi.org/10.1089/hum.2018.192
Chekuri, Anil ; Sahu, Bhubanananda ; Chavali, Venkata Ramana Murthy ; Voronchikhina, Marina ; Soto-Hermida, Angel ; Suk, John J. ; Alapati, Akhila N. ; Bartsch, Dirk Uwe ; Ayala-Ramirez, Raul ; Zenteno, Juan C. ; Dinculescu, Astra ; Jablonski, Monica ; Borooah, Shyamanga ; Ayyagari, Radha. / Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy. In: Human Gene Therapy. 2019 ; Vol. 30, No. 5. pp. 632-650.
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