Retinal-chitosan conjugates effectively deliver active chromophores to retinal photoreceptor cells in blind mice and dogs

Songqi Gao, Shirin Kahremany, Jianye Zhang, Beata Jastrzebska, Janice Querubin, Simon M. Petersen-Jones, Krzysztof Palczewski

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The retinoid (visual) cycle consists of a series of biochemical reactions needed to regenerate the visual chromophore 11-cis-retinal and sustain vision. Genetic or environmental factors affecting chromophore production can lead to blindness. Using animal models that mimic human retinal diseases, we previously demonstrated that mechanism-based pharmacological interventions can maintain vision in otherwise incurable genetic diseases of the retina. Here, we report that after 9-cis-retinal administration to lecithin:retinol acyltransferase-deficient (Lrat2/2) mice, the drug was rapidly absorbed and then cleared within 1 to 2 hours. However, when conjugated to form chitosan-9-cis-retinal, this prodrug was slowly absorbed from the gastrointestinal tract, resulting in sustainable plasma levels of 9-cis-retinol and recovery of visual function without causing elevated levels, as occurs with unconjugated drug treatment. Administration of chitosan-9-cis-retinal conjugate intravitreally in retinal pigment epithelium-specific 65 retinoid isomerase (RPE65)-deficient dogs improved photoreceptor function as assessed by electroretinography. Functional rescue was dose dependent and maintained for several weeks. Dosing via the gastrointestinal tract in canines was found ineffective, most likely due to peculiarities of vitamin A blood transport in canines. Use of the chitosan conjugate in combination with 11-cis-6-ring-retinal, a locked ring analog of 11-cis-retinal that selectively blocks rod opsin consumption of chromophore while largely sparing cone opsins, was found to prolong cone vision in Lrat2/2 mice. Development of such combination low-dose regimens to selectively prolong useful cone vision could not only expand retinal disease treatments to include Leber congenital amaurosis but also the age-related decline in human dark adaptation from progressive retinoid cycle deficiency.

Original languageEnglish
Pages (from-to)438-452
Number of pages15
JournalMolecular Pharmacology
Volume93
Issue number5
DOIs
StatePublished - May 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Funding

This research was supported in part by grants from the National Institutes of Health (EY009339, EY020551, EY027283, and EY024864 to K.P.; EY025214 to B.J.; EY024864 to K.P.; and core grants P30EY011373 and P30EY025585), and the Myers Dunlap Endowment for Canine Health to S.M.P.-J. K.P. is the John H. Hord Professor of Pharmacology. 1S.G. and S.K. contributed equally to this work. https://doi.org/10.1124/mol.117.111294. s This article has supplemental material available at molpharm. aspetjournals.org.

FundersFunder number
National Institutes of HealthEY027283, EY024864, EY009339, EY025214, P30EY011373, P30EY025585
National Eye InstituteR01EY020551

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