Alan M. Laties · University of Pennsylvania · PhdFit
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Alan M. Laties
· Professor of Ophthalmology in Neurology
University of Pennsylvania · Rehabilitation Medicine
Alan M. Laties, MD, was a Professor of Ophthalmology in Neurology at the University of Pennsylvania's Perelman School of Medicine. He completed his undergraduate education at Harvard College in 1954 and earned his MD from Baylor College of Medicine in 1959. His professional focus was in the field of ophthalmology, and he was associated with the Department of Ophthalmology at the University of Pennsylvania. The information provided indicates that he was a notable member of the faculty, contributing to the academic and clinical missions of the institution.
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Purpose: Accumulation of lysosomal waste is linked to neurodegeneration in multiple diseases, and pharmacologic enhancement of lysosomal activity is hypothesized to reduce pathology. An excessive accumulation of lysosomal-associated lipofuscin waste and an elevated lysosomal pH occur in retinal pigment epithelial cells of the ABCA4-/- mouse model of Stargardt's retinal degeneration. As treatment with the P2Y12 receptor antagonist ticagrelor was previously shown to lower lysosomal pH and lipofuscin-like autofluorescence in these cells, we asked whether oral delivery of ticagrelor also prevented photoreceptor loss. Methods: Moderate light exposure was used to accelerate photoreceptor loss in albino ABCA4-/- mice as compared to BALB/c controls. Ticagrelor (0.1%-0.15%) was added to mouse chow for between 1 and 10 months. Photoreceptor function was determined with electroretinograms, while cell survival was determined using optical coherence tomography and histology. Results: Protection by ticagrelor was demonstrated functionally by using the electroretinogram, as ticagrelor-treated ABCA4-/- mice had increased a- and b-waves compared to untreated mice. Mice receiving ticagrelor treatment had a thicker outer nuclear layer, as measured with both optical coherence tomography and histologic sections. Ticagrelor decreased expression of LAMP1, implicating enhanced lysosomal function. No signs of retinal bleeding were observed after prolonged treatment with ticagrelor. Conclusions: Oral treatment with ticagrelor protected photoreceptors in the ABCA4-/- mouse, which is consistent with enhanced lysosomal function. As mouse ticagrelor exposure levels were clinically relevant, the drug may be of benefit in preventing the loss of photoreceptors in Stargardt's disease and other neurodegenerations associated with lysosomal dysfunction.
Frontiers in Pharmacology · 2018-04-19 · 21 citations
articleOpen access
The accumulation of partially degraded lipid waste in lysosomal-related organelles may contribute to pathology in many aging diseases. The presence of these lipofuscin granules is particularly evident in the autofluorescent lysosome-associated organelles of the retinal pigmented epithelial (RPE) cells, and may be related to early stages of age-related macular degeneration (AMD). While lysosomal enzymes degrade material optimally at acidic pH levels, lysosomal pH is elevated in RPE cells from the ABCA4-/- mouse model of Stargardt’s disease, an early onset retinal degeneration. Lowering lysosomal pH through cAMP-dependent pathways decreases accumulation of autofluorescent material in RPE cells in vitro, but identification of an appropriate receptor is crucial for manipulating this pathway in vivo. As the P2Y12 receptor for ADP is coupled to the inhibitory Gi protein, we asked whether blocking the P2Y12 receptor with clinically-relevant antagonist ticagrelor could restore lysosomal acidity and reduce autofluorescence in compromised RPE cells from ABCA4-/- mice. Oral delivery of ticagrelor lowered lysosomal pH in these RPE cells. Ticagrelor also partially reduced autofluorescence in the RPE of ABCA4-/- mice. In vitro studies in ARPE-19 cells using more specific antagonists AR-C69931 and AR-C66096 confirmed the importance of the P2Y12 receptor for lowering lysosomal pH and reducing autofluorescence. These observations identify P2Y12 receptor inhibition as a potential target to lower lysosomal pH and clear lysosomal waste in RPE cells.
Journal of Neurochemistry · 2017-02-28 · 57 citations
article
Abstract Mechanical strain in neural tissues can lead to the up‐regulation and release of multiple cytokines including interleukin 6 (IL‐6). In the retina, the mechanosensitive release of ATP can autostimulate P2X7 receptors on both retinal ganglion cell neurons and optic nerve head astrocytes. Here, we asked whether the purinergic signaling contributed to the IL‐6 response to increased intraocular pressure (IOP) in vivo , and stretch or swelling in vitro . Rat and mouse eyes were exposed to non‐ischemic elevations in IOP to 50–60 mmHg for 4 h. A PCR array was used to screen cytokine changes, with quantitative (q)PCR used to confirm mRNA elevations and immunoblots used for protein levels. P2X7 antagonist Brilliant Blue G (BBG) and agonist (4‐benzoyl‐benzoyl)‐ATP (BzATP) were injected intravitreally. ELISA was used to quantify IL‐6 release from optic nerve head astrocytes or retinal ganglion cells. Receptor identity was confirmed pharmacologically and in P2X7 −/− mice, acute elevation of IOP altered retinal expression of multiple cytokine genes. Elevation of IL‐6 was greatest, with expression of IL1rn , IL24 , Tnf , Csf1 , and Lif also increased more than twofold, while expression of Tnfsf11 , Gdf9 , and Tnfsf4 were reduced. qPCR confirmed the rise in IL‐6 and extracellular ATP marker ENTPD1, but not pro‐apoptotic genes. Intravitreal injection of P2X7 receptor antagonist BBG prevented the pressure‐dependent rise in IL‐6 mRNA and protein in the rat retina, while injection of P2X7 receptor agonist BzATP was sufficient to elevate IL‐6 expression. IOP elevation increased IL‐6 in wild‐type but not P2X7R knockout mice. Application of mechanical strain to isolated optic nerve head astrocytes increased IL‐6 levels. This response was mimicked by agonist BzATP, but blocked by antagonists BBG and A839977. Stretch or BzATP led to IL‐6 release from both astrocytes and isolated retinal ganglion cells. The mechanosensitive up‐regulation and release of cytokine IL‐6 from the retina involves the P2X7 receptor, with both astrocytes and neurons contributing to the response. image
Journal of Ocular Pharmacology and Therapeutics · 2016-04-05 · 21 citations
articleOpen access1st author
Abstract Purpose: To investigate the safety, tolerability, and pharmacokinetics of trabodenoson, a highly selective adenosine mimetic targeting the adenosine A 1 receptor. Methods: In Part 1, 60 healthy adult volunteers were randomized to 14 days of twice-daily topical monocular application of placebo or trabodenoson (200, 400, 800, 1,600, 2,400, or 3,200 μg). In Part 2, 10 subjects were randomized to placebo or 8 escalating doses of bilateral trabodenoson (total daily doses: 1,800–6,400 μg). Results: The incidence of treatment-related adverse events in Part 1 was similar in the trabodenoson (27.8%) and placebo (25.0%) groups. Most were mild in intensity. The most common adverse events (AEs) for trabodenoson and placebo were headache (25.0% vs. 33%, respectively) and eye pain (11.1% vs. 4.2%, respectively). Ocular AEs were infrequent (16.7% and 17.9%, respectively), were self-limited, lasted <24 h, and were typically mild in intensity. The most common ocular AE was eye pain (9.5% and 3.6%, respectively), with a single observation of ocular hyperemia (200 μg trabodenoson). Trabodenoson was rapidly absorbed [median time to maximum concentration (t max ): ∼0.08 to 0.27 h] and eliminated (t ½ : 0.48–2.0 h), with no evidence of drug accumulation. Systemic exposure to topical trabodenoson was dose related but not dose proportional, with a plateau effect at doses ≥2,400 mg per eye. No clinically significant treatment-related systemic AEs were observed, and increasing systemic exposure had no effect on heart rate or blood pressure. Conclusions: Ocular doses of trabodenoson up to 3,200 μg per eye were safe and well tolerated in the eye and resulted in no detectable systemic effects in healthy adult volunteers.
PURPOSE: The cellular mechanisms linking elevated IOP with glaucomatous damage remain unresolved. Mechanical strains and short-term increases in IOP can trigger ATP release from retinal neurons and astrocytes, but the response to chronic IOP elevation is unknown. As excess extracellular ATP can increase inflammation and damage neurons, we asked if sustained IOP elevation was associated with a sustained increase in extracellular ATP in the posterior eye. METHODS: No ideal animal model of chronic glaucoma exists, so three different models were used. Tg-Myoc(Y437H) mice were examined at 40 weeks, while IOP was elevated in rats following injection of hypertonic saline into episcleral veins and in cynomolgus monkeys by laser photocoagulation of the trabecular meshwork. The ATP levels were measured using the luciferin-luciferase assay while levels of NTPDase1 were assessed using qPCR, immunoblots, and immunohistochemistry. RESULTS: The ATP levels were elevated in the vitreal humor of rats, mice, and primates after a sustained period of IOP elevation. The ecto-ATPase NTPDase1 was elevated in optic nerve head astrocytes exposed to extracellular ATP for an extended period. NTPDase1 was also elevated in the retinal tissue of rats, mice, and primates, and in the optic nerve of rats, with chronic elevation in IOP. CONCLUSIONS: A sustained elevation in extracellular ATP, and upregulation of NTPDase1, occurs in the posterior eye of rat, mouse, and primate models of chronic glaucoma. This suggests the elevation in extracellular ATP may be sustained in chronic glaucoma, and implies a role for altered purinergic signaling in the disease.
Modern medicine development is alike unlocking mystery of black box. The journey of 10- year drug development is about establishing a drug molecular biological trait along with its pharmacological behaviors in animal disease models and various human conditions. Product medical strategy has become ever more important in bridging gaps for translational efficiency. This review focuses on the paradigm shift of therapeutic intervention for retinal diseases. Topics include: 1) Emerging ocular drug delivery innovation from polymer-based sustained-release drug delivery to genetic engineering protein biofactory (superachoroidal and subretinal routes begin to merge). 2) New themes of tissue rejuvenation and parainflammation in retina and glaucoma disease management. 3) New highs in disease alteration by emerging therapies - the switch from “wet to dry” vascular AMD (age-related macular degeneration) is a great example of such in the new era of anti-VEGF therapy. 4) Bio-therapeutic innovation at a glance. 5) Understand disease staging and phenotype stratification is “A Must” in developing personalized treatment algorithm. New evidences suggest that AMD represents a group of heterogeneous clinical pathological entity that includes RPE aging, photoreceptor loss, Bruch’s membrane thickening, and choroid ischemia, among which one or more can be the primary trigger and predominant clinical phenotype. New appreciation of glaucoma as a neural degenerative disease involving pressure-dependent and pressure-independent risk factors may lead to breakthrough of neural protection drug development in the 21 st century. In summary, reduce photoreceptor and retinal ganglion cell loss is the ultimate goal of therapeutic intervention for a large spectrum of significant neurovascular diseases in the retina. (254 words). In the retina, there are two biggest problems spanning at two extreme ends. One end is about cell proliferation such as choroid neovascularization (CNV), proliferative vitraretinopathy (PVR), proliferative diabetic retinopathy (PDR), epiretinal or subretinal fibrosis and scar formation, as well as inflammatory cell proliferation. The other end is abnormal cell loss due to apoptotic and necrotic cell death in various genetic or acquired pathological conditions, such as age-related macular degeneration (AMD), glaucomatous neural degeneration, retinitis pigmentosa (RP) and Stargardt’s macular degeneration (SMD), for which regenerative medicine comes into a play. In the past two decades, scientific advances have allowed us to gain in-depth understanding of molecular pathophysiological mechanisms involved retinal diseases, which are changing the way of how we treat patient and how we project future medicine.
