p75NTR

Scientists in Cincinnati and Japan identify a population of progenitor cells that strongly promote new blood vessel growth in ischemic limbs at risk of amputation from diabetes and other conditions CINCINNATI, Dec. 19, 2023 /PRNewswire/ -- Across the United States, about 2 million people are living with an amputation and another 185,000 amputations occur every year, according to the Amputee Coalition, a Washington, DC-based support group. About 54% of these lost limbs were caused by vascular disease, including diabetes and peripheral arterial disease (PAD). And as more people are diagnosed with diabetes, in the U.S. and worldwide, the number of amputations keeps rising. Continue Reading Graphical abstract illustrates how CD271+ progenitor cells derived from adipose tissue can prompt limb-preserving blood vessel growth. Source: Cincinnati Children's and Cell Reports Medicine. Now, experts at Cincinnati Children's in collaboration with colleagues from Kanazawa University in Japan, have uncovered a new way to prompt blood vessel growth that shows promise as a treatment for preventing ischemia-induced amputations. Their discoveries were based on achieving a deeper understanding about why two patients in a clinical trial in Japan walked away with fully recovered limbs that appeared destined for amputation. The study, published Dec. 19, 2023, and featured as the cover article for the journal Cell Reports Medicine, was led by first author Oto Inoue, MD, PhD, a cardiologist from Japan and a research fellow with Cincinnati Children's, and Juan Sanchez-Gurmaches, PhD, Division of Endocrinology. Their team reports that a specific subset of stem cells isolated from adipose tissue (fat) that also carry the cell surface marker CD271 outperformed all other similar cell types at inducing blood vessel formation. The study also details key molecular mechanisms involved in the process. The scientists confirmed these findings by transplanting this population of human stem cells into mice with limb ischemia. In every case, the treatment rescued limbs that otherwise would have required amputation. Then the team analyzed data from a clinical trial to provide initial evidence that such a cell transplant may have already worked in humans. In this case, people with foot ulcers were treated with a generalized mix of stem cells collected from the patients' own tissues. Of the small number of patients analyzed, the two patients with fully recovered limbs received high numbers of CD271-positive stem cells. Those results in combination with the highly consistent benefits found in the mouse testing, appear to justify further work to launch a formal clinical trial, the co-authors say. "Critical limb ischemia is one of the most severe outcomes for PAD and undertreated diabetes. This research shows hopeful results that this new subset of progenitors may have positive therapeutic value," Inoue says. "It was quite inspiring to see that one of the patients has recovered enough to return to work." A race to address a widespread health problem With rising rates of obesity plaguing the United States, diabetes incidence has been rising for years, and leading to a host of cardiovascular complications, including PAD leading to critical limb ischemia. Doctors treat PAD by using medications to slow the disease while performing bypass surgeries or catheter-based procedures to open clogged arteries in the limbs. However, many of the arteries that need treatment in the limbs are too small and difficult to access with surgery. As a result, at least a third of the people who need revascularization therapy are not eligible for surgical interventions. Those who lose their limbs go on to experience significant pain and disability while their underlying cardiovascular disease makes them increasingly likely to experience potentially fatal heart attacks, strokes, and other problems. Once seen as a purely adult health problem, researchers at Cincinnati Children's and other centers have been finding early signs of vascular disease in teens and even younger children who struggle with severe obesity and diabetes. Emerging alternatives from international collaboration Inoue, 40, has been studying PAD in Japan for more than a decade. He came to Cincinnati in 2021 to further study the emerging area of induced angiogenesis through cellular transplantation as a member of the Sanchez-Gurmaches lab. Many researchers have explored the idea of transplanting progenitor cells to jump-start the body's own tissue-repair capabilities. However, the major limitation has been finding the right cells to use. To solve this, the team used single-cell transcriptomics to hunt through a haystack of different types of progenitor cells to find the right population of cells. While many stem cells reside naturally in the bone marrow, this study found the strongest trigger of blood vessel formation lurking within fat tissue. These cells carry the marker CD271, which has been shown in other studies to play important roles in tissue growth. The team transplanted these human CD271-positive cells into mice to confirm their abilities. The human CD271 cells were 100% effective at prompting enough blood vessel growth in the mice to restore normal blood flow to the diseased limbs. Evidence that this new cell population may work in human disease also was provided. The authors found that among people who received progenitor cells self-transplanted from fat, those who recovered better and saved their limbs had higher numbers of CD271 progenitor cells present. "The positive correlation between recovery and the number of CD271+ progenitors injected in the affected area of these patients was striking," Sanchez-Gurmaches says. Challenges ahead The co-authors emphasize that the findings so far are preliminary. The therapeutic value of adipose tissue CD271-positive cells should be evaluated in larger numbers of patients through a formal clinical trial. One significant issue to resolve is how to obtain enough CD271 progenitor cells to use as treatment. The new paper reports that the number of CD271 progenitors found in the fat of people with insulin resistance can be as much as 75% lower than people without insulin resistance. Also, the cells that are found tend to be less active in generating new vessels. "Unfortunately, the people living with insulin resistance who face elevated risk of limb ischemia are the same people with low numbers of CD271-postive progenitor cells, which could make self-transplantation more difficult," Inoue says. More research is needed to determine if these cells can be multiplied in the lab before transplantation. About the study In addition to Inoue and Sanchez-Gurmaches, Cincinnati Children's co-authors included PhD student Manasi Halurkar, Hee-Woong Lim, PhD, and Vivian Hwa, PhD. Funding sources for this study include the National Institutes of Health (R21OD031907); the Japan Society for the Promotion of Science (JP16H06828); the Japanese Heart Foundation; the American Heart Association (18CDA34080527), and three grants from Cincinnati Children's (a Trustee Award, a Center for Pediatric Genomics Award and a Center for Mendelian Genomics & Therapeutics Award. SOURCE Cincinnati Children's Hospital Medical Center

Study of Novel Biological Agent for Chronic Pain in Patients with Osteoarthritis SANDWICH, United Kingdom, Dec. 13, 2023 (GLOBE NEWSWIRE) -- Levicept Ltd, a biotechnology company focused on the development of LEVI-04, a first-in-class treatment for chronic pain indications, today announces it has completed recruitment in its Phase II clinical trial of LEVI-04, a novel neurotrophin-modulating biological agent. Top line data are expected to be announced in late first half of 2024. The multiple-arm, multicentre, prospective, randomized, double-blind, placebo-controlled Phase II study enrolled more than 500 participants with pain due to osteoarthritis of the knee (ClinicalTrials.gov ID: NCT05618782). The trial was designed to evaluate the efficacy, safety and tolerability of five, monthly, infusions of LEVI-04 as compared to placebo in participants with radiographic and symptomatic knee osteoarthritis. The trial is being conducted at sites across Europe and in Hong Kong, led by Dr Philip Conaghan at The School of Medicine, University of Leeds, UK. LEVI-04 modulates the neurotrophin pathway that is clinically proven to provide effective analgesia in a range of indications and is designed to minimise use-limiting side effects of anti-NGF antibodies, including rapid progression of osteoarthritis. It is a proprietary p75 neurotrophin receptor fusion protein (p75NTR-Fc). LEVI-04 is designed to deliver neurotrophin homeostasis by providing a reversible binding protein which scavenges excess neurotrophins present in chronic pain states. It operates across four receptor pathways in the neurotrophin system and is designed to supplement the existing endogenous p75NTR binding protein and returning normal neurotrophin function. Importantly, unlike anti-NGF antibodies which ablate NGF signalling as they bind irreversibly to NGF, LEVI-04 provides analgesia while maintaining the neurotrophin function required for cartilage and bone repair. Phase I data on LEVI-04 demonstrated a favourable safety, tolerability and pharmacokinetic profile. Analysis of biomarkers indicated target engagement and provided early supporting evidence of efficacy / proof-of-concept. Dr Philip Conaghan, Principal Investigatorsaid, “Safe and effective pain management is a critical need in arthritis with existing treatments limited by addiction-liabilities, adverse effects and poor efficacy. While the potential of the neurotrophin pathway to provide effective pain relief is recognised, safety issues have significantly hampered development. LEVI-04 offers a highly promising new approach to safely harness the analgesic potential of neurotrophin modulation and we look forward to the trial results next year.” Simon Westbrook, founder and CSO of Levicept, and study director said, “The fact we completed recruitment in this large-scale Phase II in under a year is testament to physicians’ interest in our programme and patients’ pressing need for new treatment options for their chronic pain.” LEVI-04 was originally discovered at Pfizer UK by Levicept’s founder, Simon Westbrook, who subsequently acquired the asset. Levicept recently announced the appointment of experienced biotech executive Eliot Forster as CEO to help steer the best path for the further development of LEVI-04 and its ultimate commercialisation. Levicept Eliot Forster, CEO – info@levicept.com Media Enquiries: Charles Consultants Sue Charles - Sue@charles-consultants.com +44 (0)7968 726585 Chris Gardner - Chris@CGComms.onmicrosoft.com +44 (0)7956 031077 About Levicept – Levicept Ltd is a UK-based biotechnology company developing a novel, safe and efficacious biological therapy (LEVI-04 [p75NTR-Fc]) for the treatment of chronic pain. LEVI-04 is currently in phase II in patients with osteoarthritis of the knee. LEVI-04 modulates the neurotrophin pathway, clinically proven to provide effective analgesia in a range of indications and is designed to minimise use-limiting side effects of anti-NGF antibodies, including rapid progression of osteoarthritis. It is estimated that the market opportunity for drugs that modulate neurotrophins, developed to a high safety standard, is worth in excess of $10 billion. LEVI-04 was originally discovered at Pfizer by Levicept’s founder, Simon Westbrook, who subsequently acquired the asset. Levicept’s investors include Medicxi, Advent Life Sciences, Gilde Healthcare and Pfizer Ventures. Follow us on LinkedIn -