THBS2

BENGALURU, India--(BUSINESS WIRE)-- Stempeutics, a leader in allogeneic cellular medicines for inflammatory diseases, announced the publication of the Knee OA Phase 3 trial results in the premier journal, the American Journal of Sports Medicine (AJSM). The results of the randomized, double-blind, controlled study in 146 patients showed that single injection of Stempeucel-OA (bone marrow-derived mesenchymal stromal cells) significantly improved WOMAC total score compared with the placebo group at 6 and 12 months, and also significantly improved WOMAC pain, stiffness, and physical function sub-scores as well as VAS scores at 6 and 12 months. MRI T2 mapping showed no worsening of deep cartilage in the medial femorotibial compartment of the knee in the Stempeucel-OA group at the 12-month follow-up, whereas in the placebo group, there was significant and gradual worsening of cartilage. Details of the Phase 3 study can be accessed in the paper published: Professor Dr Vivek Pandey, MS (Kasturba Medical College, Manipal, India), who was part of Phase 3 clinical trial, said, “We are encouraged by the study data at one year follow up that indicate the potential of allogeneic cellular therapy to address the major areas of unmet need in Knee Osteoarthritis in young patients where conventional treatments provide only temporary pain relief and do not alter the disease course. Stempeucel®-OA, based on the Phase 3 trial data at one-year follow-up, has the potential to provide best-in-class pain reduction, improve stiffness, improves physical function, improve quality of life, and has the potential to regenerate/maintain cartilage and stall further disease progression for Grade 2 & Grade 3 Osteoarthritis patients based on the Kellgren and Lawrence radiographic criteria.” “These provocative results may usher in new directions for the field of cell-based regenerative therapies in the coming decade,” stated Dr Nikhil Verma, MD (Rush University Medical Center, Chicago, Illinois), who made a poster presentation at American Orthopaedic Society of Sports Medicine Conference at Colorado Springs, US in 2022. Stempeutics has analysed the potency of Stempeucel-OA by their ability to secrete pro-chondrogenic factors such as TSP-2. As osteoarthritis is a degenerative disease associated with the loss of cartilage, we believe that the presence of these molecules in the secretome of MSCs affects the clinical outcome. TSP-2 is an extracellular matrix protein that plays a major role in determining the chondrogenic differentiation potential of MSCs and stimulates the differentiation of endogenous chondroprogenitor cells. Dr Pawan Gupta, President, Medical & Regulatory Affairs, Stempeutics, said, "The Stempeucel-OA product is developed from Stempeucel® Technology, i.e. Bone Marrow-Derived, Cultured Pooled, Allogeneic Mesenchymal Stromal Cells. We have administered Stempeucel-OA using ultrasound guidance and used T2 mapping MRI techniques to assess the quality of articular cartilage. We are delighted to see statistically significant data on our primary endpoint, i.e., the change from baseline to one year in the WOMAC Osteoarthritis Composite Index score compared to the placebo arm.”

An international team of researchers has discovered a new genetic mutation that leads to childhood glaucoma, and in the process, uncovered a new mechanism for causing the disease. They hope their findings can lead to better screening for families affected by this devastating condition and one day new treatments. An international team of scientists led by Mass Eye and Ear, a member of Mass General Brigham, and Boston Children's Hospital, has discovered a new genetic mutation that may be a root cause of severe cases of childhood glaucoma, a devastating condition that runs in families and can rob children of their vision by 3 years of age. Through advanced genome-sequencing technology, the researchers found a mutation in the thrombospondin-1 (THBS1) gene in three ethnically and geographically diverse families with childhood glaucoma histories. The researchers then confirmed their findings in a mouse model that possessed the genetic mutation and went on to develop symptoms of glaucoma driven by a previously unknown disease mechanism. The new findings, published December 1 in the Journal of Clinical Investigation, could lead to improved screening for childhood glaucoma and earlier and more targeted treatments to prevent vision loss in children with the mutation, according to the study's authors. "This is a very exciting finding for families affected by childhood glaucoma," said Janey L. Wiggs, MD, PhD, Associate Chief of Ophthalmology Clinical Research at Mass Eye and Ear and the Vice Chair for Ophthalmology Clinical Research and Paul Austin Chandler Professor of Ophthalmology at Harvard Medical School. "With this new knowledge, we can offer genetic testing to identify children in a family who may be at risk for the disease and start disease surveillance and conventional treatments earlier to preserve their vision. In the future, we would look to develop new therapies to target this genetic mutation." Leading cause of childhood blindness Childhood, or congenital, glaucoma is a rare but serious disease that presents in children as early as birth and as late as 3 years of age. Despite its rarity, childhood glaucoma is responsible for 5 percent of cases of child blindness worldwide. Glaucoma causes irreversible damage to the eye's optic nerve, often due to buildup of pressure inside the eye (intraocular pressure, or IOP). In adults, this damage can occur over time without symptoms, which is why the disease is often referred to as a "sneak thief of sight." Children and babies with childhood glaucoma, however, can be born with severe disease and vision loss or lose their vision later in childhood due to elevated IOP. This increase in pressure not only damages the optic nerve but can also affect other structures in a child's eye like the cornea. Children with childhood glaucoma typically require surgeries as early as the first three to six months of life, followed by several more operations throughout their childhood. With childhood glaucoma, there is typically a strong hereditary component often with multiple members of a family affected by the condition. According to Dr. Wiggs, by better understanding the genes involved, genetic testing can give affected families peace of mind to learn whether their child might be at risk for developing the disease. Uncovering the genetic underpinnings of disease For decades, researchers have turned towards genetics to better understand the cause of glaucoma. When Dr. Wiggs first began this line of research 30 years ago, scientists were only able to identify regions of the genome affected in glaucoma. Thanks to advances in genomic technology, researchers gained the ability to review the complete genetic makeup of individuals with and without glaucoma to determine which specific genetic mutations play a role in the disease. Research led by Dr. Wiggs in 2021 used a dataset of more than 34,000 adults with glaucoma to identify 127 genes associated with the condition. To better study the genetic mutations in childhood glaucoma, Dr. Wiggs and her Mass Eye and Ear team first looked at exome sequences from an American family of European-Caucasian descent who had been part of an earlier research project and found a striking and novel variant in thrombospondin-1, a well-known protein in the body involved in a number of important biological processes, such as the formation of new vessels (angiogenesis) and tissues. This mutated gene was not found in people without childhood glaucoma, nor in large population genetic databases. The amino acid altered by the mutation was evolutionarily conserved, indicating an important role in the protein function. This finding led Dr. Wiggs to connect with colleagues at Flinders University in Australia to see if they had any childhood glaucoma families with thrombospondin mutations. They surprisingly found two families with an alteration at the same amino acid: one of mixed European and Indian descent, and one Sudanese family originally from Africa. "What was really striking about this finding is that these families all possessed this genetic variant, and it was not possible for them to be related because they were from such diverse backgrounds," said Dr. Wiggs. "That meant there was something really important about this mutation." To further test this hypothesis, the researchers collaborated with Robert J. D'Amato, MD, PhD, the Judah Folkman Chair in Surgery in the Vascular Biology Program at Boston Children's Hospital, and a professor of Ophthalmology at Harvard Medical School. Dr. D'Amato's team developed a mouse model with the THBS1 mutation and found that the mouse also had features of glaucoma. "Thrombospondin-1 is well known as a potent inhibitor of blood vessel growth, or angiogenesis," said Dr. D'Amato, who has studied angiogenesis for more than three decades. "I assumed at first that THBS1 mutations were disrupting blood vessel formation in the eye, but our animal models showed normal angiogenesis. We realized that there must be another mechanism." Specifically, D'Amato's lab showed that the mutation caused abnormal thrombospondin proteins to accumulate in the intraocular drainage structures of the eye involved with regulating IOP, which in turn, led to a buildup of pressure that damaged the optic nerve and led to the loss of retinal ganglion cells, thereby causing vision loss. This was the first time that researchers identified this kind of disease mechanism for causing childhood glaucoma. "This work highlights the power of international collaborations," said study co-author Owen M. Siggs MD, DPhil, associate professor at Flinders University and the Garvan Institute of Medical Research in Australia. "There's such incredible genetic diversity across the globe, and comparing this information is becoming more and more critical for discoveries like this." Personalizing care for families with future study The new study has significant clinical implications, according to the researchers. While more work remains before comprehensive genetic testing can be offered, every gene that is found presents another opportunity to be able to identify causative mutations in these families through screening, according to the authors. Therapeutically, knowledge of this gene mutation can lead to earlier treatments with conventional therapies. For example, if a baby is born with this mutation, their eye care specialist can better inform the parents of the risks and develop an appropriate disease-monitoring and treatment plan. Identifying this new mechanism and gene at the root of childhood glaucoma could also lead to new therapies that would target the accumulation of abnormal proteins. The researchers also aim to determine if other THBS1 mutations are involved in adult-onset disease, like primary open-angle glaucoma, or milder forms of the disease if the mutation is not as pronounced. The researchers will also continue to look for new genes associated with childhood glaucoma in the hopes of one day developing very comprehensive screening. "Dr. Wiggs is an international expert in glaucoma genetics and has worked tirelessly to unravel the genetic contributions to these blinding diseases. These findings provide important insights into the causes of childhood glaucoma and offer the prospect of targeted therapy," said Joan W. Miller, MD, Chair of Ophthalmology at Mass Eye and Ear and Massachusetts General Hospital, Ophthalmologist-in-Chief at Brigham and Women's Hospital, and Chair of Ophthalmology and the David Glendenning Cogan Professor of Ophthalmology at Harvard Medical School. "The collaboration is a powerful demonstration of the strength of bedside-to-bench-to-bedside translational research, in uncovering disease pathogenesis and developing therapies for patients." In addition to Drs. Wiggs, D'Amato and Siggs, co-authors of the study included Haojie Fu, Lachlan S.W. Knight, Sandra E. Staffieri, Jonathan B. Ruddle, Amy E. Birsner, E. Ryan Collantes and Jamie E. Craig. This study was funded in part by the March of Dimes foundation, the National Institutes of Health (grants R01EY031820 and P30EY014104), the Ophthalmic Research Institute of Australia, the Channel Seven Children's Research Foundation, the Department of Innovation, Industry, Science and Research (Australia) and the National Health and Medical Research Council of Australia. In addition, this work was supported by the Boston Children's Hospital Mouse Gene Manipulation Core funded by NIH/NICHD U54 HD090255 and NIH R01 NS38253.

Observing how cells are organised in mucinous ovarian cancer can lead to new treatment options, study shows. A global study into mucinous ovarian cancer could help oncologists recommend the best treatment for women who are diagnosed early with the condition. By looking down a microscope for two different 'patterns of invasion' -- the way that cancer cells invade ovarian tissue -- oncologists can better predict which patients may have better or worse prognoses and can target treatment accordingly. The finding was reported in a paper published today in Clinical Cancer Research, a journal of the American Association for Cancer Research. "Mucinous ovarian cancer is a rare type of ovarian cancer. It actually has more in common with gastrointestinal cancers, and can be hard to diagnose and hard to treat once it has spread beyond the ovaries," says lead author Nicki Meagher, who has just completed her PhD in the Molecular Oncology group, UNSW School of Clinical Medicine. She says that observing which of the two types of invasion patterns that the cancer cells form could help specialists decide on treatment strategies. "We've shown for the first time that women who have early-stage disease -- meaning they have tumours that haven't spread beyond the ovary -- have much poorer survival chances in the first two years from diagnosis if they have what we call an infiltrative pattern of invasion. "Knowing this in the early stage of the disease means we can identify patients who could benefit from additional chemotherapy following surgery to remove their ovaries." The two patterns of invasion are defined by the way the cancer cells organise themselves when viewed under a microscope. The infiltrative pattern of invasion associated with poorer health outcomes shows cancer cells spreading in an uneven, haphazard way through the ovarian tissue. The other pattern is known as expansile, where cells expand through tissue in a more orderly manner, and is associated with better prognoses. Up until now, other studies had suggested that the infiltrative pattern of invasion was associated with poorer patient outcomes, but no study had large enough numbers of patients with early-stage cancer to reach statistical significance. But the current study, that involved more than 100 researchers in Australia, UK, Canada, Asia, Europe and the US, was able to test this hypothesis in much larger numbers by examining the tissue of 604 patients. The researchers also looked for the expression of 19 genes including THBS2 and TAGLN in addition to the patterns of invasion. Professor Susan Ramus who oversaw the global study and heads the Ovarian Tumour Tissue Analysis consortium says that guidelines on how to treat women with early-stage mucinous ovarian cancer have differed around the world due to limited data on infiltrative patterns of invasion associated with survival rates. "For example, in some parts of the world, an infiltrative pattern was acknowledged as an important feature and determined what treatment those women receive," Professor Ramus says. "Whereas in others, all patients are recommended for the same pathway of treatment. We hope that after this large study treatment guidelines can be aligned and that we can target treatment for women who may have these more serious indicators, even if they are diagnosed in early stages." The researchers also noted that women with higher expression of two genes, THBS2 and TAGLN in their tumours, had poorer overall survival. "We're hoping that this may be able to help explain some of the biology potentially down the track," says Ms Meagher. "Another avenue could be that knowledge of expression of these genes could assist in developing targeted drugs." The researchers are part of a wide network of experts who plan to carry out a validation study to further investigate these genomic markers as the basis for a targeted treatment strategy.