Manganese-Enhanced MRI for Preclinical Evaluation of Retinal Degeneration Treatments

Schur, Rebecca; Sheng, Li; Sahu, Bhubanananda; Yu, Guan‐Ping; Gao, Songqi; Yu, Xin; Maeda, Akiko; Palczewski, Krzysztof; Zhang, Lu

doi:10.1167/iovs.15-16522

Cited by 13 publications

(16 citation statements)

References 35 publications

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“…Images of mouse retinal structures were obtained in vivo with ultra‐high‐resolution spectral domain‐optical coherence tomography (OCT) (Envisu C2200; Bioptigen, Irvine, CA, USA) (53). Images were acquired 3 d after treatment and exposure to light, with follow‐up images acquired after 8 d. Before imaging, mice were anesthetized by injection of a cocktail (10 μl/g body weight, i.p.)…”

Section: Methodsmentioning

confidence: 99%

New GABA modulators protect photoreceptor cells from light‐induced degeneration in mouse models

Schur

Gao

et al. 2018

FASEB j.

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No clinically approved therapies are currently available that prevent the onset of photoreceptor death in retinal degeneration. Signaling between retinal neurons is regulated by the release and uptake of neurotransmitters, wherein GABA is the main inhibitory neurotransmitter. In this work, novel 3-chloropropiophenone derivatives and the clinical anticonvulsants tiagabine and vigabatrin were tested to modulate GABA signaling and protect against light-induced retinal degeneration. Abca4Rdh8 mice, an accelerated model of retinal degeneration, were exposed to intense light after prophylactic injections of one of these compounds. Imaging and functional assessments of the retina indicated that these compounds successfully protected photoreceptor cells from degeneration to maintain a full-visual-field response. Furthermore, these compounds demonstrated a strong safety profile in wild-type mice and did not compromise visual function or damage the retina, despite repeated administration. These results indicate that modulating inhibitory GABA signaling can offer prophylactic protection against light-induced retinal degeneration.-Schur, R. M., Gao, S., Yu, G., Chen, Y., Maeda, A., Palczewski, K., Lu, Z.-R. New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models.

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Section: Methodsmentioning

confidence: 99%

New GABA modulators protect photoreceptor cells from light‐induced degeneration in mouse models

Schur

Gao

et al. 2018

FASEB j.

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“…Electroretinograms were acquired according to a reported method 44 . Animals were anesthetized by intraperitoneal injection of a cocktail (15 μL/g body weight) comprised of ketamine (6 mg/mL) and xylazine (0.44 mg/mL) in PBS buffer (10 mM sodium phosphate and 100 mM NaCl [pH 7.2]).…”

Section: Methodsmentioning

confidence: 99%

Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis

Sun

Sahu

Gao

et al. 2017

Molecular Therapy - Nucleic Acids

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Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber’s congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC). All-trans-retinylamine, which binds to interphotoreceptor retinoid-binding protein (IRBP), was incorporated into the nanoparticles via a polyethylene glycol (PEG) spacer for targeted delivery of pDNA into the retinal pigmented epithelium. The targeted ECO/pDNA nanoparticles provided high GFP expression in the RPE of 1-month-old Rpe65−/− mice after subretinal injection. Such mice also exhibited a significant increase in electroretinographic activity, and this therapeutic effect continued for at least 120 days. A safety study in wild-type BALB/c mice indicated no irreversible retinal damage following subretinal injection of these targeted nanoparticles. All-trans-retinylamine-modified ECO/pDNA nanoparticles provide a promising non-viral platform for safe and effective treatment of RPE-specific monogenic eye diseases such as LCA2.

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“…Berkowitz et al did not detect a significant difference in the signal intensity in the light/dark states between the inner and outer layers of the retina on conventional MRI, but MEMRI revealed that the change in signal intensity between light/dark conditions was significantly greater in the outer layer of the retina than that in the inner layer of the retina, facilitating observations of the physiological response of the normal retina (133). MEMRI was also used to assess changes in retinal function and post-treatment efficacy by measuring ion channel activity (134). In addition to displaying changes in retinal function, MEMRI reveals changes in the retinal structure.…”

Section: Retinopathymentioning

confidence: 99%

Manganese-Enhanced Magnetic Resonance Imaging: Application in Central Nervous System Diseases

Yang

2020

Front. Neurol.

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Manganese-enhanced magnetic resonance imaging (MEMRI) relies on the strong paramagnetism of Mn 2+. Mn 2+ is a calcium ion analog and can enter excitable cells through voltage-gated calcium channels. Mn 2+ can be transported along the axons of neurons via microtubule-based fast axonal transport. Based on these properties, MEMRI is used to describe neuroanatomical structures, monitor neural activity, and evaluate axonal transport rates. The application of MEMRI in preclinical animal models of central nervous system (CNS) diseases can provide more information for the study of disease mechanisms. In this article, we provide a brief review of MEMRI use in CNS diseases ranging from neurodegenerative diseases to brain injury and spinal cord injury.

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Manganese-Enhanced MRI for Preclinical Evaluation of Retinal Degeneration Treatments

Abstract: Manganese-enhanced MRI has the potential to assess the response of the retina to prophylactic treatment based on the measurement of ion channel activity. This approach could be used as a complementary tool in preclinical development of new prophylactic therapies for retinopathies.

Cited by 13 publications

References 35 publications

New GABA modulators protect photoreceptor cells from light‐induced degeneration in mouse models

New GABA modulators protect photoreceptor cells from light‐induced degeneration in mouse models

Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis

Manganese-Enhanced Magnetic Resonance Imaging: Application in Central Nervous System Diseases

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