Light in retinitis pigmentosa

Kennan, Avril; Aherne, Aileen; Humphries, Pete

doi:10.1016/j.tig.2004.12.001

Cited by 123 publications

(97 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Why AVP misfolded mutants are cytotoxic to AVP-producing neurons is an unresolved issue. Protein misfolding, an "unfolded protein response" in cells, and the accumulation of excess misfolded protein leading to apoptotic cell death are well documented for autosomal dominant retinitis pigmentosa (36).…”

Section: Inherited Neurohypophyseal Diabetes Insipidus (Omim 125700) mentioning

confidence: 99%

Molecular Biology of Hereditary Diabetes Insipidus

Fujiwara

Bichet

2005

Journal of the American Society of Nephrology

223

150

View full text Add to dashboard Cite

A nyone who passes large volumes of urine might be said to be experiencing diabetes insipidus. Years ago, the initial distinction made by physicians in evaluating patients with polyuria was whether their urine was sweet (diabetes mellitus) or not (diabetes insipidus) (1). Diabetes insipidus is a disorder characterized by the excretion of abnormally large volumes (Ͼ30 ml/kg body wt/d for adults) of dilute urine (Ͻ250 mmol/kg). This definition excludes osmotic diuresis, which occurs when excess solute is being excreted, for example, glucose in the polyuria of diabetes mellitus. Four basic defects can be involved: (1) deficient secretion of the antidiuretic hormone arginine vasopressin (AVP), which is the most common defect and is referred to as neurohypophyseal (also known to as neurogenic, central, or hypothalamic) diabetes insipidus; (2) renal insensitivity to the antidiuretic effect of AVP, which is known as nephrogenic diabetes insipidus (NDI); (3) excessive water intake that can result in polyuria, which is referred to as primary polydipsia; and (4) increased metabolism of vasopressin during pregnancy, which is referred to as gestational diabetes insipidus. The hereditary forms of diabetes insipidus account for Ͻ10% of the cases of diabetes insipidus seen in clinical practice. The purpose of this review is to examine recent developments in the understanding and molecular biology of the hereditary forms of diabetes insipidus. Here we use the gene symbols approved by the HUGO Gene Nomenclature Committee (http://www.gene.ucl.ac.uk/nomenclature) and provide OMIM entry numbers (2). Not included in this review are acquired forms of NDI; for further information, see references 3-5. Genes Involved in "Pure" Diabetes Insipidus AVPThe regulation of the release of AVP from the posterior pituitary is primarily dependent, under normal circumstances, on tonicity information relayed by osmoreceptor cells in the anterior hypothalamus (6). AVP and its corresponding carrier, neurophysin II, are synthesized as a composite precursor by the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus (for review, see 7). The precursor is packaged into neurosecretory granules and transported axonally in the stalk of the posterior pituitary. En route to the neurohypophysis, the precursor is processed into the active hormone. Prepro-vasopressin has 164 amino acids and is encoded by the 2.5-kb AVP gene located in chromosome region 20p13 (8,9). The AVP gene (coding for AVP and neurophysin II) and the OXT gene (coding for oxytocin and neurophysin I) are located in the same chromosome region, at a very short distance from each other (12 kb in humans) in head-to-head orientation. Data from transgenic mouse studies indicate that the intergenic region between the OXT and the AVP genes contains the critical enhancer sites for cell-specific expression in the magnocellular neurons (7). It is phylogenetically interesting to note that cis and trans components of this specific cellular expression have been conserved bet...

show abstract

Section: Inherited Neurohypophyseal Diabetes Insipidus (Omim 125700) mentioning

confidence: 99%

Molecular Biology of Hereditary Diabetes Insipidus

Fujiwara

Bichet

2005

Journal of the American Society of Nephrology

223

150

View full text Add to dashboard Cite

show abstract

“…Theoretically, even in late stages of the disease, patients with measurable foveal structure could benefit from gene transfer, even if targeted exclusively to this retinal region. Experience with other retinal degenerative diseases that lead to loss of peripheral and rod photoreceptor-mediated vision, such as forms of retinitis pigmentosa (Kennan et al, 2005), indicates that even a small island of retained conemediated vision can allow patients to maintain more independence and quality of life than without this function (Szlyk et Non-ocular tissues Heart -----------Lung nd nd -------ϩ(534) -Liver -----------Pancreas -----------Spleen -----------Kidney -----------Jejunum -----------Gonads -------…”

Section: Figmentioning

confidence: 99%

Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

et al. 2006

View full text Add to dashboard Cite

Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision has been restored by subretinal delivery of AAV-RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies of subretinal AAV-2/2. RPE65 in RPE65 -mutant dogs showed evidence of modest photoreceptor loss in the injection region in some animals at higher vector doses. We now test the hypothesis that there can be vectorrelated toxicity to the normal monkey, with its human-like retina. Good Laboratory Practice safety studies following single intraocular injections of AAV-2/2. RPE65 in normal cynomolgus monkeys were performed for 1-week and 3-month durations. Systemic toxicity was not identified. Ocular-specific studies included clinical examinations, electroretinography, and retinal histopathology. Signs of ocular inflammation postinjection had almost disappeared by 1 week. At 3 months, electroretinography in vector-injected eyes was no different than in vehicle-injected control eyes or compared with presurgical recordings. Healed sites of retinal perforation from subretinal injections were noted clinically and by histopathology. Foveal architecture in subretinally injected eyes, vector or vehicle, could be abnormal. Morphometry of central retina showed no photoreceptor layer thickness abnormalities occurring in a dose-dependent manner. Vector sequences were present in the injected retina, vitreous, and optic nerve at 1 week but not consistently in the brain. At 3 months, there were no vector sequences in optic nerve and brain. The results allow for consideration of an upper range for no observed adverse effect level in future human trials of subretinal AAV-2/2. RPE65. The potential value of foveal treatment for LCA and other retinal degenerations warrants further research into how to achieve gene transfer without retinal injury from surgical detachment of the retina. KeywordsLeber congenital amaurosis, blindness, mutated dogs, retina, injection, dogs and safety data with rAAV-2/2.RPE65. Questions about systemic and retinal toxicity are asked in a nonhuman primate, the only mammal with a foveate retina like that of humans, to determine whether there is sufficient safety to initiate human clinical trials.

show abstract

“…Included in this array of genes is phosphodiesterase-6b (pde6b), mutations in which account for 4-5% of autosomal-recessive cases. Pde6b codes for cGMP-specific phosphodiesterase 6b, an essential component in the rod signal transduction pathway, triggered by photon absorption (Cote 2004;Kennan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa

Roche

Wyse-Jackson²,

Byrne³

et al. 2016

Int. J. Dev. Biol.

View full text Add to dashboard Cite

Mouse models of retinitis pigmentosa (RP) are essential tools in the pursuit to understand fully what cell types and processes underlie the degeneration observed in RP. Knowledge of these processes is required if we are to develop successful therapies to treat this currently incurable disease. We have used the rd10 mouse model of RP to study retinal morphology prior to photoreceptor loss, using immunohistochemistry and confocal microscopy on cryosections, since little is known about how the mutation affects the retina during this period. We report novel findings that the mutation in the rd10 mouse results in retinal abnormalities earlier than was previously thought. Defects in rod and cone outer segments, bipolar cells, amacrine cells and photoreceptor synapses were apparent in the retina during early stages of postnatal retinal development and prior to the loss of photoreceptors. Additionally, we observed a dramatic response of glial cells during this period. Microglia responded as early as postnatal day (P) 5; ~13 days before any photoreceptor loss is detected with Müller glia and astrocytes exhibiting changes from P10 and P15 respectively. Overall, these findings present pathological aspects to the postnatal development of the rd10 retina, contributing significantly to our understanding of disease onset and progression in the rd10 mouse and provide a valuable resource for the study of retinal dystrophies.

show abstract

Light in retinitis pigmentosa

Cited by 123 publications

References 58 publications

Molecular Biology of Hereditary Diabetes Insipidus

Molecular Biology of Hereditary Diabetes Insipidus

Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa

Contact Info

Product

Resources

About