CR1

Currently, a lot is known about which genes are responsible for our individual blood groups, however not much is understood about how and why the levels of the blood group molecules differ between one person and another. This can be important for blood transfusion safety. Now a research group has developed a toolbox that finds the answer – and in doing so, has solved a 50-year-old mystery. Currently, a lot is known about which genes are responsible for our individual blood groups, however not much is understood about how and why the levels of the blood group molecules differ between one person and another. This can be important for blood transfusion safety. Now a research group at Lund University in Sweden has developed a toolbox that finds the answer -- and in doing so, has solved a 50-year-old mystery. The study was published recently in Nature Communications. For the past 30 years, the research group in Lund has studied the genetic basis of our many blood groups and their research has laid the foundation of six new blood group systems. On the surface of the red blood cell are found proteins and carbohydrates that are very similar between people. However, small differences in these molecules have been shown to be due to genetic variants that encode what we know as blood group antigens. What has not been understood until now is why people with the same blood group can have different amounts of a certain blood group antigen on their red blood cells. "This is important, because if you only have a couple of hundred blood group molecules per cell instead of a thousand or even a million molecules, then there is a risk that they maybe missed in a blood compatibility test, which can affect the safety of a blood transfusion," explains Martin L Olsson, professor in Transfusion Medicine at Lund University, and consultant within Clinical Immunology and Transfusion Medicine, Region Skåne, who has led the project. Since routine genetic analysis could not answer this question, the research group turned its attention to a group of proteins called transcription factors. These are molecules that can recognise different "landing" sites in DNA and work a little like a light switch to turn off/turn down genes or get them to express more strongly. Thus, transcription factors are important for the production of different proteins in the cells. With the help of a series of bioinformatics tools (together called a pipeline) developed by PhD student, Gloria Wu, the researchers could localise nearly 200 landing sites for transcription factors in 33 different blood group genes in our DNA. Then, to test the pipeline to see if the predictions were correct, the group investigated one of the most important transcription factors for red blood cell development to see if there was a genetic change in one of these landing sites. This could give the reason for why a certain blood group was downregulated to a low level. Tested on an unsolved blood group mystery To see how the results could be used, the researchers focused on a blood group variant called Helgeson, in which the red blood cell has unusually little of a molecule called Complement Receptor 1 (CR1), an important protein for our immune response. The Helgeson blood group has been a mystery that has eluded the research world for a long time. Approximately 1% of the population has this blood group but it hasn't even been possible to detect it with the help of DNA techniques. In addition, the mechanism behind the low CR1 expression has remained unexplained. "Margaret Helgeson was a medical technologist in Minneapolis in the 1970s who was trying to find compatible blood for a patient in need of a blood transfusion. Despite her best efforts she could not find any suitable blood units. In desperation, she tested her own blood, and to her surprise, found it to be a match," recounted Jill Storry, adjunct professor of experimental transfusion medicine at Lund University and one of the researchers behind the study. This is how the blood group became known as Helgeson. But why does a small group of people have this weak blood group? It turns out that blood donors and patients with the Helgeson blood group have a low CR1 expression because of a genetic variation in the landing site DNA sequence for an important transcription factor. This means the transcription factor cannot bind where it should and drive the production of CR1. "Now the gene simply idles. In our study, we also showed this genetic variant to be more common in Thai blood donors compared with Swedish blood donors, which makes sense since we know from previous studies that a lower CR1 level is protective against malaria," explains Martin L Olsson. So, while it's difficult to detect a lower expression of CR1 in the transfusion laboratory, it gives protection against malaria, especially in areas such as Southeast Asia where the disease is common. Thanks to this study, we now understand the mechanisms behind the Helgeson blood group and why it can be more difficult to detect in certain populations. "Based on what we know now, we can improve the laboratory tests. Our goal is to update the existing DNA-based chip that is used for blood group tests with the new variant, which will result in a safer diagnostic test," says Gloria Wu. The role of blood groups in disease is the next step With the help of this data-driven, bioinfomatic pipeline, which makes it possible to get a comprehensive grip on how our blood group genes are regulated, the research group can continue to apply more of their findings to other blood groups. Furthermore, the toolbox can be utilised more widely. "Much of our research on blood groups now uses a combination of data-based predictive tools that can point us to the right experiment to test in the lab. The next challenge is to better understand the function of blood groups by connecting the information from large databases on how diseases affect people differently depending on their blood group," concludes Martin L Olsson.

– Everads' next generation suprachoroidal delivery technology enables targeted drug delivery to the retina, which Kriya intends to use for multiple ophthalmology gene therapy product candidates – – Kriya is developing a one-time gene therapy designed to block complement C3 and C5, which are clinically validated substrates targeted by FDA approved therapies, to delay the progression of geographic atrophy – – Kriya anticipates advancing its geographic atrophy gene therapy candidate into the clinic in 2H 2024 – PALO ALTO, Calif. and RESEARCH TRIANGLE PARK, N.C., Sept. 27, 2023 (GLOBE NEWSWIRE) -- Kriya Therapeutics, Inc. ("Kriya"), a biopharmaceutical company developing gene therapies for conditions affecting millions of people around the world, has entered into an exclusive license, collaboration and supply agreement with Everads Therapy, Ltd (“Everads”) to advance Kriya’s portfolio of gene therapies for retinal diseases using Everads' suprachoroidal delivery device. Everads is a private biotech company that has developed a novel technology enabling targeted delivery of therapies to the retina via the suprachoroidal space, an anatomical compartment located between the sclera and choroid that traverses the circumference of the posterior segment of the eye. Suprachoroidal delivery is an emerging, non-surgical route of administration in ophthalmology. Specifically in delivery of gene therapy, this route of administration offers the potential to enhance the efficiency of gene therapy delivery to the retina while minimizing intraocular inflammation. The transaction enables Kriya’s access to Everads’ suprachoroidal delivery technology to deliver multiple prespecified gene therapy product candidates for several ophthalmic diseases, including those involving the complement cascade. Dysregulation of the complement system has been implicated in the pathogenesis and progression of geographic atrophy. Kriya’s approach is a one-time adeno-associated virus (AAV) gene therapy that drives the expression of a CR2-CR1 (complement receptor 2-complement receptor 1) fusion protein that is designed to inhibit complement C3 and C5. These are also targeted by the first two FDA-approved treatments for geographic atrophy which require monthly or bi-monthly intraocular injections. “We are excited about the potential to advance a gene therapy that blocks both complement C3 and C5, which are validated biological targets for the treatment of geographic atrophy,” said Shankar Ramaswamy, M.D., Co-Founder and CEO of Kriya. “Our collaboration with Everads aligns with our vision to implement next generation delivery technologies that can optimize AAV delivery to the eye via one-time administration, which has the potential to substantially reduce patient burden associated with repeated intravitreal injections or subretinal surgical approaches.” “We believe that our suprachoroidal delivery technology provides a potential leap forward for novel eye care therapies. Our proprietary, geometrically-optimized non-sharp tissue separator opens a path into the suprachoroidal space, enabling a more convenient tangential injection that can support rapid and extensive drug distribution,” said Moshe Weinstein, Executive Chair & CEO of Everads. “We are excited to partner with Kriya to enable delivery of cutting-edge gene therapy via the suprachoroidal space that may ultimately improve the quality of life for patients with geographic atrophy.” Kriya's gene therapy candidate for geographic atrophy has the following potential benefits: One-time AAV administration may substantially lower the patient burden imposed by currently approved treatments for geographic atrophy that require monthly or bimonthly intraocular injections – while also delivering multiyear efficacy in the setting of a progressive degenerative disease;Continuous expression of the CR2-CR1 fusion protein results in potent inhibition of the complement cascade by the CR1 domain designed to block C3 and C5, while also through the action of the CR2 domain, targeting this inhibition to the site of complement fragment deposition on damaged cell surfaces; andAdministration via the suprachoroidal space has the potential to maximize transduction of retinal cells while minimizing inflammation that can be associated with intravitreal and other routes of administration. “Geographic atrophy causes a debilitating loss of vision that can dramatically impact the lives of patients—we are in dire need of effective and conveniently administered therapies that slow or halt the progression of this disease,” said Quan Dong Nguyen, M.D., M.Sc., FARVO, FASRS, Professor of Ophthalmology at the Byers Eye Institute, and Professor of Medicine and Professor of Pediatrics at Stanford University School of Medicine. “I am quite optimistic and convinced that innovative therapies will continue to improve the lives of people with geographic atrophy and other serious ophthalmic diseases. A gene therapy targeting the C3 and C5 pathways delivered by a suprachoroidal injection may be a significant improvement in the treatment of geographic atrophy.” About Geographic Atrophy (GA)Geographic Atrophy is an advanced form of dry age-related macular degeneration (dry AMD) and affects approximately 1 million people in the United States. It is caused by the growth of lesions, which destroy the retinal cells responsible for vision, resulting in progressive and irreversible vision loss. People suffering from geographic atrophy experience blind spots, impaired facial recognition, decreased reading and low light driving ability, severely impairing their independence and quality of life. Geographic atrophy accounts for 20% of cases of legal blindness in North America. (Sources: Rudnicka. Ophthalmol. 2012; Wong. Lancet Glob Health. 2014; Patel. Clin Opthalmol. 2020.) About Kriya TherapeuticsOur mission is to revolutionize medicine, with the ultimate goal of eliminating human suffering and enabling people to live without the burden of disease. Kriya is a biopharmaceutical company developing gene therapies to address diseases affecting millions of people around the world. With operations in Palo Alto, California and Research Triangle Park, North Carolina, Kriya has raised over $600 million in committed capital, which will be used to advance a broad pipeline of gene therapies for ophthalmology, neurology and metabolic disease. For more information, please visit www.kriyatx.com and follow us on LinkedIn and X (Formerly Twitter). About Everads TherapyEverads Therapy is a biotech company focused on optimizing treatment of retinal diseases using its proprietary suprachoroidal delivery technology. With the aim of overcoming challenges in current treatment methodologies for retinal and macular diseases, Everads' delivery platform offers the promise of improving the efficacy and safety of existing and potential drug therapies via suprachoroidal delivery. Everads has a number of collaborations in the areas of gene therapy, cell therapy, small molecule formulations and other modalities. Everads was spun out of DALI Medical Devices, a company specializing in development of injectable drug delivery technologies, and established within RAD Biomed, a leading biotech incubator in Israel. Everads’ underlying technologies were licensed from the Sheba Tel Hashomer Medical Center/Sheba Impact. For more information, please visit www.everads-therapy.com and follow us on LinkedIn.

Researchers have identified several genetic variants associated with increased risk of cancer in children with non-chromosomal birth defects, such as congenital heart disease and defects of the central nervous system. While the risk of developing cancer is not as high as children with chromosomal birth defects, it is significantly higher than children with no birth defects at all, and the findings may provide a basis for early detection in these understudied patients. Researchers from Children's Hospital of Philadelphia (CHOP) have identified several genetic variants associated with increased risk of cancer in children with non-chromosomal birth defects, such as congenital heart disease and defects of the central nervous system. While the risk of developing cancer is not as high as children with chromosomal birth defects, it is significantly higher than children with no birth defects at all, and the findings may provide a basis for early detection in these understudied patients. The findings were recently published in the journal Biomarker Research. Children with birth defects are more likely to develop cancer, and that increased risk of cancer persists into adulthood. Prior studies have demonstrated that children with chromosomal birth defects, such as Down syndrome and Klinefelter syndrome, are more than 11 times more likely to be diagnosed with cancer than children without any birth defects. However, children with non-chromosomal birth defects are up to 2.5 times more likely to be diagnosed with cancer than those without birth defects. With birth defects of any kind occurring in 1 in every 33 births in the United States each year, that increased risk implicates a significant number of children. The underlying genetics of non-chromosomal birth defects have not been studied in great detail. Researchers at the Center for Applied Genomics (CAG) at CHOP wanted to determine what molecular mechanisms were at play and potentially identify genetic clues that could lead to early identification of cancer in these patients. "We assembled one of the largest pediatric oncology and birth defects projects in children as part of the Gabriella Miller Kids First program project, which helps to uncover new insights into childhood cancer and structural birth defects," said Hakon Hakonarson, MD, PhD, director of the CAG at CHOP and senior author of the study. "With this partnership, we sought to identify functional molecular pathways based on mutations we identified as part of this study." In this study, researchers used data obtained from whole genome sequencing of blood samples from 1,653 individuals without chromosomal abnormalities that were acquired from the Kids First Data Resource Center. These samples included 541 birth defect probands -- the first person in a family to receive genetic counseling or testing for hereditary risk of a disease -- with at least one type of malignant tumor, 767 birth defect probands without malignant tumors, and 345 healthy family members who are parents or siblings of the aforementioned probands. Additionally, once variants were identified, whole genome sequencing data from 40 birth defect probands from outside the data resource center, including 25 patients with at least one type of cancer, were used to further validate the study. The study identified thousands of variants of interest, including 119 genes with at least two variants in coding regions -- regions of the gene that will eventually be transcribed and translated into proteins to carry out essential functions -- and 478 genes with at least 20 variants in their non-coding regions. Five genes in particular -- AXIN2, BMP1, CR1, ERBB2, and RYR1 - are associated with birth defects and increased risk of cancer. Additionally, the researchers built a deep learning model to assess the variants of interest identified in the Kids First cohort when compared with the 40 validation samples and found that they had achieved approximately 75% accuracy, with even greater accuracy for variants that were associated with non-coding regions. Further detailed analysis of this data could identify genes and noncoding mutations that not only result in specific birth defects but also identify which types of cancer they are more prone to and whether the risk is more pronounced in childhood or adulthood. "While more research is needed to delve into the variants of interest we identified, this study represents a critical step toward the earlier detection of cancer children with non-chromosomal birth defects," Hakonarson said. The sequencing data was provided through the Gabriella Miller Kids First Pediatric Research Program consortium (Kids First), supported by the Common Fund of the Office of the Director of the National Institutes of Health. The study was supported by Institutional Development Funds from CHOP to the CAG.