Tag: Vision Loss

  • Minocycline fails to slow vision loss in people with dry age-related macular degeneration

    Minocycline fails to slow vision loss in people with dry age-related macular degeneration

    [ad_1]

    The drug minocycline, an antibiotic that also decreases inflammation, failed to slow vision loss or expansion of geographic atrophy in people with dry age-related macular degeneration (AMD), according to a phase II clinical study at the National Eye Institute (NEI), part of the National Institutes of Health.

    Dry AMD affects the macula, the part of the eye’s retina that allows for clear central vision. In people with dry AMD, patches of light-sensing photoreceptors and their nearby support cells begin to die off, leaving regions known as geographic atrophy. Over time, these regions expand, causing people to lose more and more of their central vision. Microglia, immune cells that help maintain tissue and clear up debris, are present at higher levels around damaged retinal regions in people with dry AMD than in people without AMD. Scientists have suggested that inflammation – and particularly microglia – may be driving the expansion of geographic atrophy regions.

    This study, led by Tiarnan Keenan, M.D., Ph.D., a Stadtman Tenure-Track Investigator at the NEI’s Division of Epidemiology and Clinical Applications, tested whether inhibiting microglia with minocycline might help slow geographic atrophy expansion and its corresponding vision loss. The trial enrolled 37 participants at the NIH Clinical Center in Bethesda, Maryland, and at the Bristol Eye Hospital, United Kingdom. After a nine-month period where the researchers tracked each participant’s rate of geographic atrophy expansion, the participants took twice-daily doses of minocycline for two years. The researchers compared each participant’s rate of geographic atrophy expansion while taking minocycline to their baseline rate, and found there was no difference in geographic atrophy expansion rate or vision loss with minocycline. 

    Previous studies have shown that minocycline can help reduce inflammation and microglial activity in the eye, including the retina. The drug has shown beneficial effects for conditions such as diabetic retinopathy, but has not previously been tested for dry AMD.

    The clinical study was funded by the NEI Intramural Program, and took place in part at the NIH Clinical Center. Clinical trial number NCT02564978.

    Source:

    Journal reference:

    Keenan, T. D. L., et al. (2024). Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial. JAMA Ophthalmology. doi.org/10.1001/jamaophthalmol.2024.0118.

    [ad_2]

    Source link

  • Researchers take important step toward genetic therapy for hereditary conditions

    Researchers take important step toward genetic therapy for hereditary conditions

    [ad_1]

    Researchers who work with tiny drug carriers known as lipid nanoparticles have developed a new type of material capable of reaching the lungs and the eyes, an important step toward genetic therapy for hereditary conditions like cystic fibrosis and inherited vision loss.

    Findings of the study led by Gaurav Sahay and Yulia Eygeris of the Oregon State University College of Pharmacy and Renee Ryals of Oregon Health & Science University were published today in the Proceedings of the National Academy of Sciences.

    Unlike other types of lipid nanoparticles that tend to accumulate in the liver, the ones in this study, based on the compound thiophene, are able to navigate their way to the tissues of the lungs and retina, where they deliver their therapeutic payload. The researchers refer to these new lipids as Thio-lipids.

    The collaboration demonstrated, by using animal models, the possibility of using Thio-lipids in lipid nanoparticles to deliver messenger RNA, the technology underpinning COVID-19 vaccines, to combat genetic blindness and pulmonary disease.

    These nanoparticles filled with fatty lipids can encapsulate genetic medicines like mRNA and CRISPR-Cas9 gene editors, which can be used to treat and even cure rare genetic diseases. Chemical structures of the lipids determine how potent are the lipid nanoparticles and which organ they can reach from the bloodstream.”


    Yulia Eygeris, senior research associate at OSU

    Lipids are organic compounds containing fatty tails and are found in many natural oils and waxes, and nanoparticles are tiny pieces of material ranging in size from one- to 100-billionths of a meter. Messenger RNA delivers instructions to cells for making a particular protein.

    With the coronavirus vaccines, the mRNA carried by the lipid nanoparticles instructs cells to make a harmless piece of the virus’ spike protein, which triggers an immune response from the body. 

    As a therapy for vision impairment resulting from inherited retinal degeneration, the mRNA would instruct cells in the retina – which don’t work right because of a genetic mutation – to manufacture the proteins needed for sight. Inherited retinal degeneration, commonly abbreviated to IRD, encompasses a group of disorders of varying severity and prevalence that affect one out of every few thousand people worldwide.

    An example of a genetic pulmonary condition is cystic fibrosis, a progressive disorder that results in persistent lung infection and affects 30,000 people in the U.S., with about 1,000 new cases identified every year.

    One faulty gene – the cystic fibrosis transmembrane conductance regulator, or CFTR – causes the disease, which is characterized by lung dehydration and mucus buildup that blocks the airway.

    The thiophene-based lipid nanoparticle study, which involved mice and non-human primates, stems from a $3.2 million grant to Sahay and Ryals from the National Eye Institute. The grant’s purpose is addressing limitations associated with the current primary means of delivery for gene editing: a type of virus known as adeno-associated virus, or AAV.

    “AAV has limited packaging capacity compared to lipid nanoparticles and it can prompt an immune system response,” said Sahay, a professor of pharmaceutical sciences. “It also doesn’t do fantastically well in continuing to express the enzymes the editing tool uses as molecular scissors to make cuts in the DNA to be edited.”

    Sahay calls the Thio-lipid findings “highly encouraging” but says more studies are needed, including research on the lipids’ long-term impact on retinal health.

    “But we think our results serve as a proof of concept and we will continue to explore Thio-lipids in potential treatments of pulmonary and retinal genetic diseases,” he said.

    Other OSU College of Pharmacy researchers contributing to the study were Mohit Gupta, Jeonghwan Kim, Antony Jozic, Milan Gautam, Jonas Renner, Dylan Nelson and Elissa Bloom.

    In addition to the National Eye Institute, funding and research support were provided by the Oregon National Primate Research Center and the Casey Eye Institute.

    [ad_2]

    Source link

  • Breakthrough $20 million OCT project aims to revolutionize eye health screening

    Breakthrough $20 million OCT project aims to revolutionize eye health screening

    [ad_1]

    In the United States, more than one-fourth of adults over age 40 have an eye disease, including glaucoma, cataracts or age-related macular degeneration, or a chronic health condition that affects the eyes, such as diabetic retinopathy. These conditions are a strain on an individual’s health as well as on the health-care system, yet early diagnosis and management can help to prevent more than 90% of severe vision loss.

    Chao Zhou, a professor of biomedical engineering in the McKelvey School of Engineering at Washington University in St. Louis, has been working to improve optical coherence tomography (OCT) systems that can conduct high-resolution imaging of the eyes. Now, with an up to $20 million contract from the Advanced Research Projects Agency for Health (ARPA-H), he plans to create a portable OCT system based on photonic integrated circuits (PIC) and custom-designed electronic integrated circuits that could offer advanced eye screening to many more patients and at a lower cost. The technology also could be used in other applications, such as cardiology, dermatology, dentistry, endoscopy and urology.

    The contract is part of ARPA-H’s first call for proposals for unconventional approaches to improving health outcomes across patient populations, communities, diseases and health conditions through breakthrough research and technological advancements. It is the first ARPA-H contract awarded to Washington University.

    Traditional OCT systems are expensive, complex, bulky and labor-intensive to assemble and calibrate. The proposed system would weigh a few pounds, take high-resolution 3D scans of the retina in less than a second and be a fraction of the cost of the traditional systems.

    The integration of photonic and electronic integrated circuits simplifies the assembly process and lowers production costs, making OCT more accessible to a wider range of health-care facilities and patients. Integrating components on a photonic chip also enhances overall stability and robustness, making these systems less susceptible to environmental influences and wear and tear, ensuring a longer lifespan and lower maintenance costs.”


    Chao Zhou, professor of biomedical engineering, McKelvey School of Engineering, Washington University in St. Louis

    Zhou’s group invented the space-division multiplexing optical coherence tomography (SDM-OCT), a technique that takes multiple high-definition OCT images simultaneously with a single detector and is at least 10 times faster than existing OCT scanners, which creates fewer opportunities for errors from patient movement. However, these systems required extensive time and labor to assemble components for each channel, which limited their broad use.

    With the ARPA-H funding, Zhou and collaborators will assemble the components in a photonic chip using advancements in complementary metal-oxide-semiconductor (CMOS) processes used in the semiconductor industry. This will streamline manufacturing and lower costs. Once functioning, they will conduct studies using the device on adult and pediatric patients.

    Developing a fully integrated photonic-integrated chip (PIC)-OCT system is very impactful yet also very challenging, the researchers said, so the team has divided its work into eight parts, ranging from developing components to testing. At the end of the five-year project, the team expects to have developed photonic and electronic chips and portable PIC-OCT prototypes specifically for ophthalmic imaging.

    The proposed system is more than 50 times faster than existing state-of-the-art commercial OCT systems at a fraction of the cost, the researchers said. By optimizing and integrating the photonic and electronic circuits, the researchers can create an integrated image acquisition and signal processing engine with benefits that extend into other areas of health care, such as glucose sensing and portable skin imagers.

    Collaborating with Zhou are:

    • Shu-Wei Huang, an assistant professor of electrical, computer and energy engineering and of biomedical engineering at the University of Colorado Boulder;
    • Aravind Nagulu, an assistant professor of electrical and systems engineering at the McKelvey School of Engineering;
    • Rithwick Rajagopal, MD, PhD, an associate professor of ophthalmology and visual sciences at Washington University School of Medicine;
    • Margaret Reynolds, MD, an assistant professor of ophthalmology and visual sciences at Washington University School of Medicine; and
    • Lan Yang, the Edwin H. & Florence G. Skinner Professor of electrical and systems engineering at the McKelvey School of Engineering.

    Yang said it is in her long-term interest to transform knowledge in photonics research into technologies and tangible products with a far-reaching societal impact, with health-care applications at the top of her agenda.

    “I’m excited to be part of this multidisciplinary team that aims to develop a new OCT system with capabilities and features enabled by advancements in nanofabrication processes for optoelectronic devices driven by various industries, from telecommunication to data centers and consumer electronics,” Yang said. “Our proposed portable OCT system, based on photonic integrated circuits (PIC), will provide advanced and cost-effective eye screening and extend its benefits to other medical fields.”

    Rajagopal said that eye doctors have benefitted from the diagnostic insights offered by OCT technology for the past 15 years, but the systems are limited by scan-speed and field-of-view.

    Most modern scanners can only image the very center of the retina -; the macula -; and require cooperative patients who have the mobility to maneuver into and stay steady on a desktop system for at least 30-60 seconds (or more), Rajagopal said.

    “I am enthusiastic about the potential clinical benefits offered by Dr. Zhou’s new system, as it may allow us to perform much higher-resolution scans and include simultaneous peripheral scanning in addition to the retinal center, all while taking a fraction of the time required by currently available systems,” Rajagopal said. “We may therefore be able to scan patients who are unable to cooperate for traditional ocular imaging, including young children and adults with disabilities, without the need for pupillary dilation or sedated exams.”

    The team will work with commercial foundries to fabricate the photonic and electronic integrated circuits.

    “Not only does this fully integrated PIC-OCT system outperform conventional OCT systems, but it also boasts excellent manufacturability and robustness and reduces device footprint,” Zhou said. “In addition, mass production would significantly reduce manufacturing costs, paving the way for widespread future dissemination.”

    While the team already has several U.S. and international patents related to the SDM-OCT, it is working with Washington University’s Office of Technology Management on patent applications for the improved design. They will also work with ARPA-H Project Accelerator Transition Innovation Office and with the Food & Drug Administration on regulatory considerations to clear the pathway for future clinical translation.

    “I am very excited to be part of this world-class team to pursue this ambitious project that makes OCT a true point-of-care solution,” Huang said. “It is a perfect example showing how PIC technology can be transformative in areas other than communication and computing.”

    [ad_2]

    Source link

  • New treatment targeting aging cells could offer lasting relief for diabetic macular edema

    New treatment targeting aging cells could offer lasting relief for diabetic macular edema

    [ad_1]

    A recent study published in the journal Nature Medicine showed that targeting senescent cells in the retina can be a lasting disease-modifying treatment for diabetic macular edema (DME).

    The retina is vascularized to support the higher energetic demand for vision. As such, the neural retina and associated blood vessels are susceptible to metabolic perturbations, like in diabetic retinopathy (DR). Blood-retina barrier breakdown at various stages of DR leads to DME, wherein extravasation of plasma and proteins into intra- and sub-retinal spaces causes swelling and vision loss.

    Current standard care for DME involves anti-vascular endothelial growth factor (VEGF) agents, which reduce macular edema and improve visual acuity. However, therapeutic response remains sub-optimal in most patients, with its effectiveness waning over time. Besides, while corticosteroids can effectively reduce edema, they can increase intraocular pressure. Exploring alternative safer, long-lasting, disease-modifying DME treatments can benefit patients.

    Study: Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Image Credit: Anukool Manoton / ShutterstockStudy: Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Image Credit: Anukool Manoton / Shutterstock

    The study and findings

    In the present study, researchers investigated how senescent cells contribute to DME. First, they estimated the levels of prototypical senescence-associated secretory phenotype (SASP) factors in DME patients’ vitreous. This revealed increases in interleukin (IL)-6, IL-8, and plasminogen activator inhibitor 1 (PAI1) levels in DME patients relative to controls with non-vascular pathology.

    Further, the expression of p16INK4A, a cell cycle regulator associated with senescence, in postmortem retinal sagittal sections of DME patients compared to age- and sex-matched non-diabetic control retinas. Increased p16INK4A expression was observed in the inner retina, choroidal layers, and Bruch’s membrane in retinas with DME. p16INK4A expression was confined to regions of suspected disease activity.

    Next, the researchers examined bulk RNA sequencing (RNA-seq) datasets of retinas from mice and rats with streptozotocin (STZ)-induced diabetes. Genes for cellular senescence and the SASP were positively correlated in STZ-treated animals compared to controls. For increased resolution, they assessed single-cell RNA-seq (scRNA-seq) datasets from mice with STZ-induced diabetes.

    Cone photoreceptors, endothelial cells (ECs), and Muller glia were the most transcriptionally perturbed populations compared to non-diabetic controls. Sub-clustering of ECs disclosed three distinct sub-clusters (EC1 – EC3). EC2 was predominant in diabetic retinas and was enriched for genes linked to vascular complications in diabetes and those involved in regulating cellular senescence in ECs and other cell types.

    Further experiments suggested that senescent ECs in the retina impaired barrier function. Next, whether hyperglycemia could trigger senescent phenotypes in DME was evaluated. Human retinal microvascular ECs (HRMECs) were exposed to a medium with high D-glucose (HG) or isosmotic control enantiomer (CTR). After five weeks of HG exposure, global cellular proliferation decreased by 25%, and cells with senescence-associated markers increased three-fold compared to CTR.

    Anti-apoptotic proteins such as B-cell lymphoma 2 (BCL2) and BCL-xL were induced in HG-treated HRMECs. Further, the researchers tested whether targeting BCL-xL could improve barrier function in diabetic retinas. A small-molecule inhibitor, UBX1967, was administered intravitreally to diabetic mice eight and nine weeks after STZ treatment. This significantly reduced protein levels of BCL-xL and PAI1 at 10 weeks of diabetes.

    Retinal BCL2 levels were unaltered, while transcript levels of inflammatory SASP factors were significantly reduced. Notably, UBX1967 treatment reduced retinal vascular permeability by 40% to 50%. In addition, whole-field scotopic electroretinography showed that UBX1967 treatment improved retinal function. The researchers developed UBX1325, a phosphate pro-drug with senolytic properties, as a therapeutic candidate.

    BCL-xL target engagement was confirmed for UBX0601 (active molecule of UBX1325) in senescent HRMECs. The researchers noted that apoptosis initiation through BCL-xL inhibition required senescent cells to be present. Apoptosis with BCL-xL inhibition did not occur in healthy retina. UBX1325 also decreased retinal vascular permeability (40% – 50%) in the STZ model compared to vehicle-treated controls.

    Next, the team performed a phase 1 safety and tolerability trial of UBX1325 in patients with advanced DME or neovascular age-related macular degeneration for whom anti-VEGF therapy was no longer beneficial. Intravitreal UBX1325 injection was well tolerated with no reports of inflammation. However, a few treatment-emergent adverse events (TEAEs) were observed that were deemed unrelated to UBX1325.

    TEAEs were more likely observed in patients receiving higher doses, which were considered due to their underlying disease. Initial safety assessment suggested that UBX1325 could be advanced into later-stage clinical studies. Plasma levels of UBX1325 and UBX0601 were below the lower quantification limit. Among DME patients, a single injection improved visual acuity. Higher UBX1325 doses reduced central subfield thickness.

    Conclusions

    Together, the findings illustrate that therapeutic clearance of senescent cells could result in long-term improvements in visual function in DME patients. Intravitreal administration of BCL-xL inhibitor eliminated senescent ECs, resulting in lower local inflammation and improved barrier function, ultimately augmenting visual function. Efficacy data suggested that vision improvements persist for at least six months.

    Journal reference:

    • Crespo-Garcia S, Fournier F, Diaz-Marin R, et al. Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Nat Med, 2024, DOI: 10.1038/s41591-024-02802-4, https://www.nature.com/articles/s41591-024-02802-4

    [ad_2]

    Source link