Novel endogenous glycan therapy for retinal diseases

Safety, in vitro stability, ocular pharmacokinetic modeling, and biodistribution

Shankar Swaminathan, Huiling Li, Mallika Palamoor, Walter T.Luchsinger De Obarrio, Dorababu Madhura, Bernd Meibohm, Monica Jablonski

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [3H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous∈>∈ retina∈>∈sclera/choroid∈>∈aqueous humor∈> ∈cornea∈>∈lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [3H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)311-323
Number of pages13
JournalAAPS Journal
Volume16
Issue number2
DOIs
StatePublished - Jan 1 2014

Fingerprint

Retinal Diseases
Polysaccharides
Pharmacokinetics
Safety
Therapeutics
Area Under Curve
Retina
Scintillation Counting
Photoreceptor Cells
Sclera
Choroid
Retinal Pigment Epithelium
Aqueous Humor
Macular Degeneration
In Vitro Techniques
Oligosaccharides
Hydrophobic and Hydrophilic Interactions
Feces
Liquid Chromatography
Cornea

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Novel endogenous glycan therapy for retinal diseases : Safety, in vitro stability, ocular pharmacokinetic modeling, and biodistribution. / Swaminathan, Shankar; Li, Huiling; Palamoor, Mallika; De Obarrio, Walter T.Luchsinger; Madhura, Dorababu; Meibohm, Bernd; Jablonski, Monica.

In: AAPS Journal, Vol. 16, No. 2, 01.01.2014, p. 311-323.

Research output: Contribution to journalArticle

Swaminathan, Shankar ; Li, Huiling ; Palamoor, Mallika ; De Obarrio, Walter T.Luchsinger ; Madhura, Dorababu ; Meibohm, Bernd ; Jablonski, Monica. / Novel endogenous glycan therapy for retinal diseases : Safety, in vitro stability, ocular pharmacokinetic modeling, and biodistribution. In: AAPS Journal. 2014 ; Vol. 16, No. 2. pp. 311-323.
@article{34885637291b42e898fefe5a8886859a,
title = "Novel endogenous glycan therapy for retinal diseases: Safety, in vitro stability, ocular pharmacokinetic modeling, and biodistribution",
abstract = "Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and M{\"u}ller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [3H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous∈>∈ retina∈>∈sclera/choroid∈>∈aqueous humor∈> ∈cornea∈>∈lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [3H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.",
author = "Shankar Swaminathan and Huiling Li and Mallika Palamoor and {De Obarrio}, {Walter T.Luchsinger} and Dorababu Madhura and Bernd Meibohm and Monica Jablonski",
year = "2014",
month = "1",
day = "1",
doi = "10.1208/s12248-014-9563-1",
language = "English (US)",
volume = "16",
pages = "311--323",
journal = "AAPS Journal",
issn = "1550-7416",
publisher = "Springer New York",
number = "2",

}

TY - JOUR

T1 - Novel endogenous glycan therapy for retinal diseases

T2 - Safety, in vitro stability, ocular pharmacokinetic modeling, and biodistribution

AU - Swaminathan, Shankar

AU - Li, Huiling

AU - Palamoor, Mallika

AU - De Obarrio, Walter T.Luchsinger

AU - Madhura, Dorababu

AU - Meibohm, Bernd

AU - Jablonski, Monica

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [3H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous∈>∈ retina∈>∈sclera/choroid∈>∈aqueous humor∈> ∈cornea∈>∈lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [3H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.

AB - Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [3H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous∈>∈ retina∈>∈sclera/choroid∈>∈aqueous humor∈> ∈cornea∈>∈lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [3H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.

UR - http://www.scopus.com/inward/record.url?scp=84895893654&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895893654&partnerID=8YFLogxK

U2 - 10.1208/s12248-014-9563-1

DO - 10.1208/s12248-014-9563-1

M3 - Article

VL - 16

SP - 311

EP - 323

JO - AAPS Journal

JF - AAPS Journal

SN - 1550-7416

IS - 2

ER -