Molecular genetics and functional analysis implicate CDKN2BAS1-CDKN2B involvement in POAG pathogenesis
3区 · 生物学
作者: Rathi, Sonika ; Danford, Ian ; Gudiseva, Harini V. ; Verkuil, Lana ; Pistilli, Maxwell ; Vishwakarma, Sushma ; Kaur, Inderjeet ; Dave, Tarjani Vivek ; O'Brien, Joan M. ; Chavali, Venkata R. M.
The genes in the 9p21 locus (CDKN2B-AS1 & CDKN2B) are widely associated with Primary open-angle glaucoma (POAG). However, the functional importance of this locus in POAG pathogenesis is still unexplored. This study investigated the role of CDKN2BAS1-CDKN2B axis in POAG. We observed significant association of CDKN2B-AS1 SNP rs4977756 with POAG and its endophenotypic traits (vertical cup-disc ratio (p = 0.033) and central corneal thickness (p = 0.008)) by screening African American POAG cases (n = 1567) and controls (n = 1600). A luciferase reporter assay in Human embryonic kidney 293T (HEK293T) cells revealed that the region surrounding rs4977756 likely serves as a transcriptional repressor. siRNA-mediated knockdown of CDKN2B-AS1 in HEK293T cells and trabecular meshwork (TM) cells resulted in significantly increased expression of CDKN2B, which was also observed in human POAG ocular tissues. Pathway focused qRT-PCR gene expression analysis showed increased cellular senescence, TGFβ signaling and ECM deposition in TM cells after CDKN2B-AS1 suppression. In conclusion, we report that CDKN2B-AS1 may act as a regulator, and it could function by modulating the expression of CDKN2B. In addition, increase in CDKN2B levels due to CDKN2B-AS1 suppression may result in the senescence of trabecular meshwork cells leading to POAG pathogenesis.
2016-10-01·Journal of Ocular Pharmacology and Therapeutics4区 · 医学
A Randomized Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Trabodenoson in Healthy Adult Volunteers
4区 · 医学
作者: Laties, Alan ; Rich, Cadmus C. ; Stoltz, Randall ; Humbert, Vernon ; Brickman, Chaim ; McVicar, William ; Baumgartner, Rudolf A.
To investigate the safety, tolerability, and pharmacokinetics of trabodenoson, a highly selective adenosine mimetic targeting the adenosine A1 receptor.
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).
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 (tmax): ∼0.08 to 0.27 h] and eliminated (t½: 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.
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.
2007-11-01·Progress in Retinal and Eye Research1区 · 医学
Iron homeostasis and toxicity in retinal degeneration
1区 · 医学
作者: He, Xining ; Hahn, Paul ; Iacovelli, Jared ; Wong, Robert ; King, Chih ; Bhisitkul, Robert ; Massaro-Giordano, Mina ; Dunaief, Joshua L.
Iron is essential for many metabolic processes but can also cause damage. As a potent generator of hydroxyl radical, the most reactive of the free radicals, iron can cause considerable oxidative stress. Since iron is absorbed through diet but not excreted except through menstruation, total body iron levels buildup with age. Macular iron levels increase with age, in both men and women. This iron has the potential to contribute to retinal degeneration. Here we present an overview of the evidence suggesting that iron may contribute to retinal degenerations. Intraocular iron foreign bodies cause retinal degeneration. Retinal iron buildup resulting from hereditary iron homeostasis disorders aceruloplasminemia, Friedreich's ataxia, and panthothenate kinase-associated neurodegeneration cause retinal degeneration. Mice with targeted mutation of the iron exporter ceruloplasmin have age-dependent retinal iron overload and a resulting retinal degeneration with features of age-related macular degeneration (AMD). Post mortem retinas from patients with AMD have more iron and the iron carrier transferrin than age-matched controls. Over the past 10 years much has been learned about the intricate network of proteins involved in iron handling. Many of these, including transferrin, transferrin receptor, divalent metal transporter-1, ferritin, ferroportin, ceruloplasmin, hephaestin, iron-regulatory protein, and histocompatibility leukocyte antigen class I-like protein involved in iron homeostasis (HFE) have been found in the retina. Some of these proteins have been found in the cornea and lens as well. Levels of the iron carrier transferrin are high in the aqueous and vitreous humors. The functions of these proteins in other tissues, combined with studies on cultured ocular tissues, genetically engineered mice, and eye exams on patients with hereditary iron diseases provide clues regarding their ocular functions. Iron may play a role in a broad range of ocular diseases, including glaucoma, cataract, AMD, and conditions causing intraocular hemorrhage. While iron deficiency must be prevented, the therapeutic potential of limiting iron-induced ocular oxidative damage is high. Systemic, local, or topical iron chelation with an expanding repertoire of drugs has clinical potential.
- Dr. Raymond Douglas, renowned thyroid eye disease specialist, joins the management team and brings extensive clinical and development experience across the spectrum of TED therapies
- Appointment supports the development of company's lead asset, linsitinib, through the ongoing Phase 2b/3 LIDS clinical trial and additional clinical and scientific initiatives
ANN ARBOR, Mich., Sept. 15, 2023 /PRNewswire/ -- Sling Therapeutics, Inc., a biopharmaceutical company focused on late-stage development of linsitinib, an oral small molecule for the treatment of thyroid eye disease (TED), today announced Raymond Douglas, M.D., Ph.D., a world-leading clinician and thought leader in TED who has been integral to developing therapeutics for the disease, has been appointed as Chief Scientific Officer. Dr. Douglas will lead activities to further explore linsitinib's potential for expansion to additional indications, as well as engage the broader scientific and medical community around Sling's progress in TED.
"Dr. Douglas brings decades of experience from his tenure as an oculoplastic and reconstructive surgeon and TED Treatment Specialist at Cedars-Sinai and previously at the University of Michigan. We are delighted to have Ray join our leadership team as we continue to enroll our Phase 2b/3 LIDS clinical trial," said Ryan Zeidan, Chief Executive Officer of Sling Therapeutics. "Dr. Douglas has an extensive track record in drug development for TED, as he led the development of teprotumumab, and has been the principal investigator of international clinical trials used to support its U.S. Food and Drug Administration (FDA) approval. In addition, Dr. Douglas pioneered the development of techniques used to improve the aesthetics of TED-induced facial and orbital changes. We are thrilled to have him join Sling Therapeutics to drive the scientific advancement and explore the additional potential of linsitinib and IGF-1R inhibition."
Dr. Douglas has over 15 years of clinical and developmental experience in oculoplastic diseases. His breakthrough research surrounding the key pathways in TED contributed to the development of teprotumumab, the first and only FDA-approved treatment for TED. His accomplishments enabled his clinic to be the first in the world to begin treatment of patients with teprotumumab. Dr. Douglas heads his own practice in Beverly Hills, California and was also a professor at Cedars-Sinai Hospital in Los Angeles, California, where he was the director of the orbital and TED programs. He received his M.D. from the University of Pennsylvania School of Medicine. Dr. Douglas completed his residency at the Scheie Eye Institute Penn Presbyterian and fellowship at the Jules Stein Eye Institute UCLA, and his Ph.D. in Immunology at the University of Pennsylvania.
"I am thrilled to be joining Sling Therapeutics as part of the leadership team to develop an accessible treatment option for TED," said Dr. Douglas. "TED is a debilitating disease where physical changes are pronounced and painful. Though aesthetic surgery is a path forward for some patients, there continues to be a market for those who desire a non-surgical option to improve their quality of life. I look forward to engaging with the TED scientific and medical community to bring awareness to Sling's work with linsitinib. I am excited to be advancing linsitinib through clinical development and its potential approval for TED, as well as continuing the development of linsitinib to address additional indications."
For more information about the Phase 2b/3 LIDS clinical trial, visit
About Thyroid Eye Disease (TED)
TED is a debilitating autoimmune disease that affects about 20,000 people in the U.S. per year and has a similar prevalence in Europe. Dysfunction in the IGF-1R signaling pathway leads to a prevalence of thyroid-stimulating hormone receptor autoantibodies (TSHR-Abs) that drive excess fibrous tissue growth behind the eyes. The inflammation can push the eyes forward or cause the eyes and eyelids to become red and swollen. As the disease progresses it can lead to pain, eye bulging, and double vision. TED predominantly affects women, and most frequently affects people with hyperthyroidism due to Graves' disease.
About Sling Therapeutics
Sling Therapeutics, Inc., is a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED). The company is advancing the evaluation of its lead product candidate, linsitinib, in a Phase 2b/3 clinical trial based on extensive preclinical and clinical data. Linsitinib offers the potential of a convenient oral small molecule that could significantly reduce the treatment burden for people living with TED. For more information visit .
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SAN DIEGO, Oct. 11, 2021 (GLOBE NEWSWIRE) -- Axim Biotech, Inc. (OTCQB: AXIM) (“AXIM® Biotech,” or “the Company”), an international healthcare solutions company targeting oncological, COVID-19 and dry eye disease (DED) diagnostics, today announced it has appointed Henry D. Perry, MD to its recently established Medical Advisory Board. He is the third member of the of the Medical Advisory Board that also includes Chairman Joseph Tauber and Laura Periman.
A recipient of the Life Achievement Award from the American Academy of Ophthalmology, Dr. Perry is recognized as one of the US’ leading cornea and refractive surgeons. He serves as Senior Founding Partner, Ophthalmic Consultants of Long Island as well as Chief, Cornea Service, Nassau University Medical Center, New York. He has won numerous Best Doctor awards and was recently recognized as one of the top 150 Ophthalmologists in America by "Newsweek" magazine in 2021.
“I’m thrilled,” said John W. Huemoeller II, AXIM® Biotech Chief Executive Officer. “Dr. Perry brings decades of valuable clinical and research experience that rounds out the exceptional depth of expertise of our Board’s first two members.”
“We’ve invited the nation’s top clinical surgical and research experts in ophthalmic pathology focused on Dry Eye (DED) and Ocular Surface Disease, and they continue to accept,” Huemoeller added. “I strongly believe this reflects the valuable DED diagnostic intellectual property and assets we are acquiring as well as the potential medical and economic value of our DED division to diagnose the millions of previously undiagnosed patients suffering from DED.”
Henry D. Perry, MD Summary Bio
Dr. Perry is the Senior Founding Partner of Ophthalmic Consultants of Long Island, and Chief, Cornea Service at Nassau University Medical Center, East Meadow, New York.
He earned his medical degree with honors from the University of Cincinnati College of Medicine and completed his residency at the Nassau County Medical Center and the University of Pennsylvania Scheie Eye Institute. Dr. Perry went on to earn fellowships in Ophthalmic Pathology at the Armed Forces Institute of Pathology in Washington D.C., and in cornea and external disease at the cornea service of the Massachusetts Eye and Ear Infirmary, Harvard University. He then served two years in the United States Army as Major, Medical Corps at Fort Sam Houston, San Antonio and Fort Dix, New Jersey.
Dr. Henry Perry is recognized as one of the leading cornea and refractive surgeons in the US and has written over 200 papers and chapters on corneal and refractive surgery and ophthalmic pathology. He has given over 500 invited lectures around the US and abroad including several named lectureships. He has served as medical director of the Lions Eye Bank for Long Island at Northwell Health since 1987. He serves as Senior Editor for the Journal “Cornea” and is the winner of the Honor Award, Senior Honor Award and Life Achievement Award from the American Academy of Ophthalmology. He has won numerous Best Doctor awards and was recently recognized as one of the top 150 Ophthalmologists in America by “Newsweek” magazine in 2021.
Dry Eye Disease Market
Recent estimates of the prevalence of dry eye disease are that over 26 million people in the United States and over 300 million globally suffer with dry eye disease. The prevalence is growing in both young and old adults, making it more urgent that clinicians are better able to diagnose and treat DED. As many as two-thirds of patients with symptoms of dry eye have never been diagnosed by their physician. Diagnosing DED is a challenge because of the multifactorial nature of the disease, with symptoms similar to other ocular surface conditions. It is well known that there is often a discordance between signs and symptoms, highlighting the need for more sensitive and accurate diagnostic tools.
About AXIM® Biotechnologies
Founded in 2014, AXIM® Biotechnologies, Inc. (AXIM) is a vertically integrated research and development company focused on changing the landscape of diagnosis of SARS-CoV-2 (COVID-19), dry eye disease (DED) and Oncological indications. AXIM’s COVID-19 neutralizing antibody test is the first rapid diagnostic test measuring levels of functional neutralizing antibodies that are believed to prevent SARS-CoV-2 from entering the host cells. Additionally, the Company is developing rapid diagnostic tests for the early detection of cancer and ophthalmological conditions such as DED. For more information, please visit .
The statements made by Axim Biotechnologies Inc., in this press release may be “forward-looking” in nature within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. Forward-looking statements describe Axim’s future plans, projections, strategies and expectations, and are based on assumptions and involve a number of risks and uncertainties, many of which are beyond the control of Axim Biotechnologies, Inc. Actual results could differ materially from those projected due to there being no assurance that our diagnostic candidate will be successfully shown to detect SARS-CoV-2 neutralizing antibodies, that the diagnostic candidate will be approved for use by the U.S. FDA or any equivalent foreign regulatory agency, that the diagnostic candidate can be manufactured in large quantities or that third parties with an established presence in blood collection clinics, vaccine development, employer or individual use will enter into agreements or purchase from the Company, and even if the Company’s diagnostic candidate is successful, it may generate only limited revenue and profits for the Company, including whether any of Axim’s diagnostic products will receive clearance from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies to sell its products and whether and when, if at all, they will receive final approval from the U.S. FDA or equivalent foreign regulatory agencies, the fact that there has never been a commercial diagnostic test utilizing neutralizing antibodies approved for use and various other factors detailed from time to time in Axim’s SEC reports and filings, including our Annual Report on Form 10-K filed on April 15, 2021 and other reports we the SEC, which are available at . Axim Biotechnologies, Inc., undertakes no obligation to update publicly any forward-looking statements to reflect new information, events or circumstances after the date hereof or to reflect the occurrence of unanticipated events, unless otherwise required by law.
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