Sickle Cell Disease and Genetics: Understanding the Cause and… – Sickle Cell Disease News

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As a progressive, unpredictable disease, sickle cell is a genetic condition that affects everyone differently, which can make it difficult to understand. Simply learning more about how the body works can help explain the cause of sickle cell. And with a better understanding of how this disease works and how genetics are involved, you can make informed decisions with your doctor about how to navigate treatment.

As the name implies, sickle cell disease involves your cells. Each person has trillions of cells in their body, all working together to perform functions that keep us alive. Within each cell is DNA, the molecule that contains the genetic information for our cells, including genes. Genes provide the instructions for your cells. They help make the proteins that keep us healthy by powering muscles, attacking invading bacteria, or delivering oxygen throughout the body. Since each cell in your body relies on thousands of proteins to work properly in order for the cells to function correctly, your genes are the blueprint, or instruction manual, for your body. When theres a mutation (or change) in a gene, the instructions can cause a cell or protein to not function properly and potentially cause diseasesuch as sickle cell.

Check out the video to learn more about how genes and proteins impact the symptoms and complications of sickle cell.

There are many different types of cells, but with sickle cell disease its the red blood cells, the most common type of cell in your blood, that are affected. These cells are responsible for delivering oxygen throughout the body, which fuels your organs by giving them the energy they need to function. The protein within these cells that performs this function is called hemoglobin, which is made up of beta-globin proteins and alpha-globin proteins. In order for normal adult hemoglobin (HbA) to work properly, there must be a balance of functioning beta-globin and alpha-globin. The HBB gene provides the instructions for these proteins within hemoglobin, and a mutation in that specific gene affects the instructions, causing your body to produce an abnormal form of beta-globin, such as hemoglobin sickle (HbS), which results in a person having sickle cell disease or carrying the sickle cell trait.

Since sickle cell disease affects everyone differently, its important to develop a comprehensive care plan that works for you and your healthcare team. This plan should aim to monitor symptoms, address chronic complications, and manage your overall health. Its also important to build a healthcare team that includes specialists from different areas who can make your care plan work for you. This team should include your primary care doctor but can also include a hematologist (who specializes in diseases of the blood), a genetic counselor (who can help with family planning), and a community health worker (who may be able to assist you with education and day-to-day monitoring by working with local hospitals), among others.

Pain, fatigue, and other unpredictable symptoms of sickle cell can affect many different aspects of your life. The daily tasks of family life, work, and/or school, as well as future plans, can all be impacted by symptoms and complications, whether theyre sudden (acute) or ongoing (chronic). Knowing how to manage these symptoms and complications can help you or your loved ones better navigate sickle cell care.

Progress continues to be made in the treatment of sickle cell disease, but current options mainly help relieve symptoms and require lifelong use. These treatment options include oral medications and infusions, blood transfusions, and, for a limited number of patients, a hematopoietic stem cell transplant (which can lead to a cure; however, they are mostly limited to people who are under the age of 18 and have a matched-related donor available).

There are also developing therapies now being explored to address unmet needs in the management and treatment of sickle cell. One therapy approach being researched is gene therapy,* which is designed to treat sickle cell at the genetic level with the goal of changing the course of the disease.

Taking the time to educate yourself on the genetics of sickle cell is an important step in managing sickle celland remember, youre not alone. Beyond your loved ones and care team, there is an entire sickle cell community, including advocacy organizations, who are here to help. For more information, visit SparkSickleCellChange.com, a website developed by bluebird bio, to stay proactive in sickle cell care and planning for the future.

*Gene therapies for sickle cell are investigational and not FDA approved. Safety and efficacy have not been established.

bluebird bio is a trademark of bluebird bio, Inc.

2023 bluebird bio, Inc. All rights reserved. SCD-US-00280 08/23

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Sickle Cell Disease and Genetics: Understanding the Cause and... - Sickle Cell Disease News

Gene-editing therapy by Vertex and CRISPR poised for FDA approval – The Boston Globe

Its kind of surreal, said Tornyenu, 22, who grew up in Bethlehem, Pa., and participated in a clinical trial at Childrens Hospital of Philadelphia. Im, like, wait, I dont have sickle cell anymore.

The life-changing drug, developed by Boston-based Vertex and its Swiss partner CRISPR Therapeutics, is expected to be approved by the Food and Drug Administration by Friday for people with severe cases of the disease. Called Casgevy, it would usher in a new era not only for those with sickle cell but also for medicine: The drug would be the first gene-editing therapy authorized by US regulators, and uses a tool called CRISPR.

The likely approval Casgevy was cleared by British regulators last month raises both the promise of cures for diseases as well as the ethical concerns that come with the power to manipulate the building blocks of human life. With an expected price tag in the seven figures, it also touches on issues of equity in medicine.

Sickle cell primarily afflicts people of African descent. Research on the disease languished for decades, which many experts blame on structural racism, particularly in funding.

For Tornyenu, Casgevy has meant an end to the searing pain crises that caused her to miss a week of classes every month as a high school senior. After getting the treatment, she took the spring semester off from Cornell to recover from the debilitating effects of chemotherapy that made room in her blood marrow for gene-edited cells.

But now she no longer dreads the arrival of cold weather, which would often induce excruciating pain in her hips and legs. A senior at Cornell, she has a job lined up as a consultant at PricewaterhouseCoopers in Boston after graduation.

Im very hopeful [Casgevy] will be approved, she said, because I dont know what I would have done otherwise.

The gene-editing method that became known as CRISPR was first reported in a landmark 2012 paper by American biochemist Jennifer Doudna of the University of California, Berkeley, and French microbiologist Emmanuelle Charpentier of the Max Planck Institute for Infection Biology. They would share the 2020 Nobel Prize in chemistry for their work on the tool.

Sickle cell was an obvious choice for scientists to tackle with CRISPR. It was the first human disorder understood on a molecular level, its underpinnings explained in a landmark 1949 paper written by the future two-time Nobel laureate Linus Pauling. Yet progress against the disease was slow for decades afterward.

Sickle cell affects hemoglobin, the oxygen-carrying protein in red blood cells. It causes the round, flexible blood cells to deform into a sickle shape and stick to vessel walls. That deprives tissues of oxygen, causing crushing pain that can often only be relieved with opioids and blood transfusions.

Sickle cell can also lead to strokes, damage organs, and cause early death. A 2019 study in JAMA Network Open estimated the life expectancy of adults with sickle cell in the US is 54 years, about 20 years shorter than the general population.

In a clinical trial, Casgevy demonstrated remarkable results. The medicine completely relieved 29 of 30 sickle cell patients of debilitating episodes of pain for at least one year among trial participants who were followed for at least 18 months, according to Vertex. The patients received a one-time intravenous infusion of edited stem cells that flipped a genetic switch to restore their blood cells ability to carry oxygen throughout their bodies.

This is what a potential cure looks like, said Dr. Stephan Grupp, chief of the Cellular Therapy and Transplant Section at Childrens Hospital of Philadelphia. He was the principal investigator at the trial site where Tornyenu got Casgevy and was paid by Vertex to help organize the study at locations across the US.

About 100,000 Americans, most of them Black or Hispanic, are believed to have sickle cell. The Vertex-CRISPR treatment was geared for those with severe and repeated pain crises, roughly 20,000 people in the US. As of 2021, almost 8 million people around the world live with sickle cell, according to the Institute for Health Metrics and Evaluation at the University of Washington in Seattle.

The FDA has approved four medicines for the disorder, but none has been remotely as effective as Casgevy, which is expected to cost more than $1 million for a one-time infusion in the US, according to experts. (No price has been announced in the United Kingdom.) Sickle cell can be cured with a bone-marrow transplant, but few patients have compatible donors.

Patients are already inquiring about Casgevy, said Dr. Sharl Azar, a hematologist at Massachusetts General Hospital and medical director of its Comprehensive Sickle Cell Disease Treatment Center. He said he is eager to see whether the FDA clears it, how broad the approval would be, and whether Medicare and Medicaid would cover it.

Theres a lot of unknowns that were looking forward to working out in the coming months, he said. But I think everyone, from patients to providers, recognizes that this is a big deal.

Rahman Oladigbolu, a 52-year-old Harvard-educated filmmaker in Brockton, is among local patients interested in Casgevy. He has had six joints his hips, shoulders, and knees surgically replaced since 2000 because of damage from sickle cell. He walks with a cane at times, often gets lightheaded, and takes opioids to relieve persistent pain.

When Oladigbolu was growing up in Nigeria, his grandmother would take him to traditional medicine men and medicine women who prescribed herbs and potions, some of which they rubbed into his aching limbs after cutting him with a razor blade. He moved to the US when he was 28 and currently takes a sickle cell drug called crizanlizumab, which reduces his pain but doesnt eliminate it.

Pursuing a cure has been like a side job all my life, said Oladigbolu, who receives treatment at Boston Medical Center.

CRISPR-based treatments will likely be approved for other disorders in the coming years, experts say, although its hard to predict for what and when. Researchers, including scientists at multiple biotech companies and hospitals in Massachusetts, are studying the potential of gene editing for a variety of diseases, from ALS to forms of cancer.

There will be other gene-editing therapies, certainly, but each disease is different, said Dr. Stuart Orkin, a researcher at Dana-Farber Cancer Institute and Boston Childrens Hospital who in 2008 helped identify the gene that Casgevy snips to treat sickle cell. For some diseases, its not clear what to edit. People will argue about whats the right target. Each one is a special case.

Gene editing has also raised ethical concerns. In 2018, a Chinese scientist, He Jiankui, was widely condemned when he announced that he used CRISPR to edit DNA in human embryos to try to make them immune to HIV. The experiment sparked fears that He had opened the door to creating so-called designer babies children whose genetic makeup is altered to produce desired traits.

Dr. George Q. Daley, dean of Harvard Medical School, was among those who said Hes experiment raised the specter of a Brave New World of eugenics. Casgevy, he said recently, is completely different. The modifications it makes to DNA only helps sickle cell patients and cannot be passed on to their children.

Daleys bigger worry concerns access to Casgevy. While wealthy countries like the US have hospitals and doctors capable of preparing patients for the treatment and administering it, he said, millions of people with sickle cell in sub-Saharan Africa dont have those options.

This is a triumph of modern biomedicine, he said. The major ethical concerns now are issues of cost and equitable distribution.

Casgevy isnt the only gene-based medicine on the horizon for sickle cell. The Somerville biotech Bluebird Bio hopes the FDA approves a so-called gene therapy, lovo-cel, by Dec. 20. It also proved remarkably effective in clinical trials.

Unlike Casgevy, which cuts a gene, lovo-cel adds a modified gene into a patients DNA to enable blood cells to deliver oxygen. The FDA has approved at least eight gene therapies for mostly rare diseases since 2017.

Both Casgevy and lovo-cel are expected to be breathtakingly expensive. That has renewed questions about whether the health care system can afford such cutting-edge medicines.

Still, the Institute for Clinical and Economic Review, or ICER, an independent Boston-based drug-pricing watchdog, estimates that either drug could cost nearly $2 million and be worth it, given the cumulative costs of treating sickle cell over a lifetime and the benefits the new approaches would bring to patients and families.

Casgevy, which was called exa-cel in clinical trials, works by editing a patients bone marrow stem cells to make high levels of fetal hemoglobin the healthy, oxygen-carrying form of hemoglobin produced during fetal development that is replaced by adult hemoglobin soon after birth.

Unlike adult hemoglobin, fetal hemoglobin resists forming a crescent shape in sickle cell patients, and scientists have long searched for a way to restart it. The researchers behind Casgevy solved the problem by editing a gene called BCL11A, which regulates fetal hemoglobin.

The treatment involves multiple steps over several months. Patients must donate stem cells to be modified at a laboratory. Then donors have to undergo a grueling regimen of chemotherapy to make room in their bone marrow for the genetically altered cells. Finally, the patients get the cells back through a single infusion.

Dr. David Altshuler, Vertexs chief scientific officer, acknowledged that the gene-editing treatment is extremely complex and resource intensive. He said Vertex is researching the possibility of developing a pill that could do what Casgevy does without gene editing. (Vertexs business partner for Casgevy, CRISPR Therapeutics, is based in Zug, Switzerland, but has most of its workforce in Boston.)

FDA officials have raised concerns about the possibility that Casgevy could inadvertently change patients DNA beyond the targeted disease so-called off-target editing. Dr. Daniel E. Bauer, a staff physician at Dana-Farber Cancer Institute and Boston Childrens Hospital, told an FDA advisory panel on Oct. 31 that Casgevy contains hundreds of millions of edited cells and one could undoubtedly go off target and cause leukemia. But he described the risk as modest given the benefits of the treatment.

Altshuler said recently that there is no evidence to date of off-target editing, but it is important to be humble and to continue to follow patients. Vertex and CRISPR have pledged to follow trial participants for 15 years to make sure they stay healthy.

Tornyenu, the Cornell student, says she considers Casgevy a miracle and would celebrate Dec. 8 every year if the FDA approves the drug that day.

For lack of a better term, she said, its a big FU to sickle cell.

Jonathan Saltzman can be reached at jonathan.saltzman@globe.com.

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Gene-editing therapy by Vertex and CRISPR poised for FDA approval - The Boston Globe

Science Talk – I survived cancer as a child and now I’m working to … – The Institute of Cancer Research

Image: Andrew Wicks in the lab at The Institute of Cancer Research. Credit: Andrew Wicks.

I still remember getting my diagnosis, even though it was all a bit of a whirlwind. Within a couple of days, Id gone from having a cough to having cancer. These things come at you fast!

At 12, I was very active and loved sports. That summer, I spent most of my time playing football or rugby, or doing athletics at school. I developed a persistent cough, but because I seemed so well otherwise, my family and I didnt think much of it. When the antibiotics the doctors had given me didnt work and I was sent to the local hospital for a chest X-ray, we assumed an infection was to blame.

Instead, the X-ray revealed a visible tumour the size of an orange in the lymph nodes around my lungs. Suspecting lymphoma, the doctors put me in an ambulance and sent me to Great Ormond Street Hospital, a childrens hospital in London. There, I had a bone marrow biopsy, which showed that I actually had acute lymphoblastic leukaemia (ALL).

ALL is a type of blood cancer that results from the bone marrow making too many immature white blood cells called lymphocytes. Many of the initial symptoms, including fatigue, frequent infections, and a fever, are nonspecific, but its important to start treatment immediately. Without treatment, the disease progresses very quickly and is fatal.

I didnt really digest the news at first. I was too numb, too shocked to be scared. I just went into autopilot and tried to adapt to the situation as it rapidly changed. However, I vividly remember my parents being scared and upset. They were devastated by my diagnosis.

Luckily, because leukaemia is the most common type of cancer in children, and ALL is the most common type of leukaemia at this age, doctors know how to treat it.

Image: Andrew aged 12, before receiving the ALL diagnosis. Credit: Andrew Wicks.

I started on high-dose chemotherapy, which was very intense. It made me feel nauseated and fatigued, and it weakened my immune system. For a year, long hospital stays and my low immunity meant that I was unable to go to school or anywhere else really. Most of the time, I felt too poorly to leave the house anyway. But I missed seeing my friends, having a social life and playing sports. My mum stopped working so that she could stay at home with me and take care of me, and my dad took a lot of time out from work so that he could be at my hospital visits.

My trips out were mainly to the hospital, which I visited at least once a week. I underwent procedures such as bone marrow biopsies and lumbar punctures, and I received chemotherapy as an outpatient there. Now, as an adult, I can reflect on how tough the treatment was, but at the time, I tried to keep a positive mindset, focusing on taking each day at a time and getting through it. To me, each treatment or hospital visit meant that I was taking a step closer to the finish.

Once I moved onto maintenance therapy, I was able to return to school, and my mum went back to work. The side effects of the treatment were more manageable, and my life started to feel a bit closer to normal. I was able to see my friends again and to go into town. But then, in the third year of my treatment, my ALL relapsed. I felt very dispirited because treatment had been going so well, but my doctors still had hope.

I needed to try a new form of treatment, so they recommended that I undergo a stem cell transplant. I had to have high-dose chemotherapy and radiotherapy to deplete my immune system before the transplant. Then I had to take immunosuppressive drugs to prevent my immune system from rejecting the donor cells and to prevent the donor cells from attacking healthy cells in my body.

Again, I had to be really careful to protect myself from infection while my immunity was low. I ended up taking some of my GCSE exams while in hospital for treatment because I was stubbornly determined not to let it disrupt the normality that had seemed so close. But it felt like a step backwards.

Thats why, when I had finally the long-desired appointment in which they told me that I was done with treatment and would only need to see the team again for checkups, my first feeling was just incredible relief. Were here, I remember thinking. Weve made it! It was such a happy moment for my family. My parents, two brothers and sister had all gone through it too. My diagnosis and treatment were tough for everyone.

Image: Andrew receiving stem cells in the hospital. Credit: Andrew Wicks.

The support and care I received from hospital staff and my family were incredible, and I cant express enough how much that helped me.

With hindsight, I was probably quite an annoying patient! Seeing lots of other people with cancer and hearing about many different treatments meant that I always had lots of questions. What is this drug? I would ask. How does it work? I took part in clinical trials during my treatment and, even as a young patient, I was intrigued by how research leads to new treatments.

Three years after completing treatment, I chose to study biology as an undergraduate. Learning about cancer in detail the different types of the disease and how it develops and progresses furthered my interest, and I went on to complete a Masters degree focused on cancer drug resistance. Wanting to get some research experience and learn even more about cancer, I joined The Institute of Cancer Research, London, as a Scientific Officer (technician) in Professor Chris Lords labin the Division of Breast Cancer Research.

I learned a lot during this time from my colleagues, who are among the leaders in their field. I knew that, given the expertise and breadth of knowledge in the team, there would be nowhere better for me to learn and undertake my own independent research project.

I am now in the fourth year of my PhD here at The Institute of Cancer Research (ICR). Supervised by Professor Lord and Professor Andrew Tutt, Head of the Division of Breast Cancer Research and Director of the Breast Cancer Now Toby Robins Research Centre at theICR, I am working on a project investigating PARP inhibitors. In particular, I am studying how tumour cells react and change when exposed to these agents, and how these changes might confer drug resistance. The long-term aim is being able to prevent or treat this resistant disease.

This years ICR Christmas fundraising appeal features the story of Tommy Edwards, a seven-year-old who is currently responding well to treatment for ALL, the same type of cancer I had.

Tommys parents, Jo and Chris Edwards, have set up a charity called Prevent ALL, which is funding work by the highly-honoured Professor Sir Mel Greaves, Founding Director of the ICRs Centre for Evolution and Cancer. Professor Greaves research shows that leukaemia, including ALL, may be preventable, and his team is working towards developing simple and safe interventions to stop the disease from developing.

All of us at the ICR are incredibly grateful for the support we receive from our amazing family charity partners like Prevent ALL. Without them, a lot of the work we do would not be possible.

Cancer is hard for everyone, including family members. In my experience, its important, where possible, to have moments where the focus on the disease is temporarily put to the side and you are just a family, as you were before the diagnosis. I hope that Tommy and his family have the opportunity to do just that this Christmas.

We are world-leaders in the study of cancer in children, teenagers and young adults and have made huge strides over the past decade in understanding the causes and improving treatments. With your support, we can make the hope of safer, kinder and more effective treatments a reality for these children. Help cure more children with cancer, more kindly.

Make a monthly donation today

Image: Tommy Edwards. Credit:ICR/John Angerson.

We still have much to learn about childhood cancer, but it is clearly not the same as adult cancer. Ideally, we should be treating it accordingly. We need treatments that are targeted to children and more appropriate for their needs.

Although the priority is, rightly, to provide treatments that are as effective as possible, in an ideal world, they would be much kinder too.

While I feel exceedingly fortunate that my treatment was successful, the debilitating side effects cost me at least a year of my childhood. Kinder treatments could allow children to go to school, see their friends and generally have a life outside of their illness. I believe that improving the quality of life for children with cancer is nothing short of essential.

At the ICR, Ive seen with my own eyes the strong connection between work in the labs and the resulting benefits for patients. The translational aspect of the ICRs work means that it has a direct impact on people. I find it very motivating to work at an institution that is so well-placed to change clinical practice for the better.

Although I dont work in the field of paediatric cancer, when I think back to my childhood, it makes me feel really positive about my career choice. Knowing that my current research might go on to help others who find themselves facing a cancer diagnosis means that I look forward to Monday mornings.

Im hopeful that, one day, outcomes can be improved for everyone living with cancer, and Im proud to be contributing to this mission. The important thing is that we keep going.

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Science Talk - I survived cancer as a child and now I'm working to ... - The Institute of Cancer Research

Major Breakthrough: UofM Research Team 3D Prints Heart Valves – Mirage News

Credit: CHU Sainte-Justine

In a breakthrough in pediatric cardiac science, Canadian researchers have successfully produced a bio-ink that could someday be used to print functional, durable heart valves, offering hope for improving the prognosis of children with heart defects.

The discovery of a way to 3D print functional heart valves was made at the CHU Sainte-Justine Research Centre by Universit de Montral assistant medical professor Houman Savoji and his PhD student Arman Jafari.

The results of their research are published in the journal Advanced Functional Materials.

Tissue engineering can be used to create living tissues and organs by combining biomaterials with cells. Unlike mechanical heart valves, engineered biomimetic valves could develop and grow with the recipients. Such tissues and organs could someday be manufactured with a 3D printer, with the right bio-ink such as that developed by Savoji and his colleagues.

Houman Savoji and Arman Jafari

Credit: CHU Sainte-Justine

"My team has shown that an ink composed of polyvinyl alcohol, gelatin and k-carrageenan can be used to print heart valves that open and close correctly and has in-vitro and in-vivo biocompatibility and anti-thrombogenic properties," he explained. "They function well in a physiological environment like that of the human body, in both adult and children's sizes."

This compound also provides a structure (called a "scaffold") in which stem cells can potentially grow until they are replaced by a fully living tissue. Better still, in laboratory tests the valves generated fewer adverse effects than the mechanical or animal valves currently used in patients.

"These results suggest that our valves may be associated with a lower risk of complications than those currently used in transplants," said Jafari. "And since these are biomimetic artificial tissues, they can potentially grow with a transplanted child, limiting the need for repeat surgery."

Over the next few years, the scientists plan to pursue their research through in vivo trials, with the ultimate goal of seeing this technology one day be made available for use in a real-life, surgical setting.

Credit: CHU Sainte-Justine

Credit: CHU Sainte-Justine

Credit: CHU Sainte-Justine

"Formulation and evaluation of PVA/gelatin/carrageenan inks for 3D printing and development of tissue-engineered heart valves," by Aman Jafari et al, was published Oct. 10, 2023 in Advanced Functional Material. Funding was provided by the Fonds de recherche du Qubec - Sant, the Natural Sciences and Engineering Research Council of Canada, the TransMedTech Institute, the CHU Sainte-Justine Research Centre and Universit de Montral. The Savoji lab also benefits from equipment funded by CHU Sainte-Justine Foundation. Arman Jafari also received a doctoral scholarship from the FRQS and a bursary of excellence from Universit de Montral's Faculty of Medicine.

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Major Breakthrough: UofM Research Team 3D Prints Heart Valves - Mirage News

Initiation of scutellum-derived callus is regulated by an embryo-like … – Nature.com

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Grnenthal and King’s College London collaborate to develop human induced pluripotent stem cell-based microfluidic cultures for pain research – Yahoo…

Dr Ramin Raouf from King's College London and Grnenthal strive to develop reliable microfluidic culture models relevant for pain research based on human induced pluripotent stem cell-derived neurons

Grnenthal has expertise in developing human induced pluripotent stem cells towards sensory neurones and will support the lab of Dr Raouf with a total consideration of more than 350.000.

AACHEN, Germany and LONDON, April 27, 2023 /PRNewswire/ -- Grnenthal and King's College London announced a 24 months collaboration to develop microfluidic culture (MFC) models based on human induced pluripotent stem cells (iPSCs) and tailored to pain research. The collaboration aims to build on Dr Ramin Raouf's pioneering work on MFCs by establishing models using human iPSC-derived neurons that closely mimic the functionality of human nociceptive neurones. Grnenthal will support the lab of Dr Raouf with its competencies in characterising human iPSCs and a total consideration of more than 350.000.

The collaboration aims to address a significant need for better transational models in pain research. Traditional rodent behavioural models have frequently failed to translate into the clinical setting due to fundamental differences in molecular, cellular and genetic mechanisms of pain across species. As a result, there is a high interest in establishing pre-clinical models that can more accurately represent the conditions in the human body. Chronic pain is a considerable burden that impacts up to one in five people worldwide and is the most common reason for seeking medical help. It stresses healthcare systems and economies, while patients frequently experience limited efficacy from available medicines.

"Compared to traditional cell culture techniques, microfluidic cultures replicate more accurately the anatomy and physiology of the nervous system. Therefore, they can provide significant advantages in pre-clinical pain research", says Dr Ramin Raouf, Lecturer in Molecular Neuroscience at King's College London. "I believe adapting them with human iPSCs will create a transformative platform for generating translatable insights into the mechanisms of pain which will eventually contribute to reducing the attrition rate in clinical development."

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"We are delighted to join forces with Dr Ramin Raouf, a leading expert in microfluidic culture models. Taking this method to the next level may significantly enhance our understanding of how investigational medicines modulate pain", says Jan Adams, M.D., Chief Scientific Officer Grnenthal. "As a leading company in pain research, our ambition is to play a crucial role in developing such pioneering methodologies. We aim to anchor these competencies in our organisation and to include such models in our pre-clinical repertoire."

Grnenthal and Dr Ramin Raouf share a common research interest in neuroscience and the investigation of mechanisms of pathological pain. Dr Ramin Raouf is a world-leading researcher in the field of microfluidic cultures who pioneered the use of microfluidic culture models to study nociceptive neurons and established sophisticated rodent models. Grnenthal is a global leader in pain research and management and has delivered six essential treatment options for pain patients in the last decades. Today, the company is dedicated to creating the next generation of innovative non-opioid pain treatments. For R&D, Grnenthal executes a distinctive therapeutic area strategy focusing on four key pain indications: peripheral neuropathic pain, chronic post-surgical pain, chronic low back pain, and osteoarthritis.

About induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) are derived from a somatic cell that has been reprogrammed back into a pluripotent state by either introducing specific genes coding for transcription factors or adding small molecules that regulate cell identity. Those iPSCs can be differentiated into different cell types with unique characters, including peripheral sensory neurons.

About microfluidic cultures

Microfluidic devices are compartmentalised chips consisting of different chambers, sometimes called lab on a chip or 'tissue chips', allowing cell-to-cell contact via a series of connecting channels.Microfluidic cultures are used in this present collaboration to investigate the effects of analgesic compounds on different cellular compartments of the pain-sensing neuronal network, as well as the communication between neurons involved in pathological pain signalling.

About Grnenthal

Grnenthal is a global leader in pain management and related diseases. As a science-based, privately-owned pharmaceutical company, we have a long track record of bringing innovative treatments and state-of-the-art technologies to patients worldwide. Our purpose is to change lives for the better, and innovation is our passion. We are focusing all our activities and efforts on working towards our vision of a world free of pain.

Grnenthal is headquartered in Aachen, Germany, and has affiliates in 28 countries across Europe, Latin America, and the U.S. Our products are available in approx. 100 countries. In 2022, Grnenthal employed around 4,400 people and achieved revenues of 1.7 bn.

More information: http://www.grunenthal.com

Follow us on:

LinkedIn: Grunenthal Group

Instagram: grunenthal

About King's College London and the Institute of Psychiatry, Psychology & Neuroscience

King's College London is one of the top 35 universities in the world and one of the top 10 in Europe (QS World University Rankings, 2021/22) and among the oldest in England. King's has more than 33,000 students (including more than 12,800 postgraduates) from over 150 countries worldwide, and 8,500 staff. King's has an outstanding reputation for world-class teaching and cutting-edge research.

The Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's is a leading centre for mental health and neuroscience research in Europe. It produces more highly cited outputs (top 1% citations) onpsychiatry andmental health than any other centre(SciVal2021),and on this metric has risen from 16th (2014) to 4th (2021) in the world for highly cited neuroscience outputs.In the 2021 Research Excellence Framework (REF),90% of research at the IoPPN was deemed 'world leading' or 'internationally excellent' (3* and 4*). World-leading research from the IoPPN has made, and continues to make, an impact on how we understand, prevent and treat mental illness, neurological conditions, and other conditions that affect the brain.

http://www.kcl.ac.uk/ioppn | Follow @KingsIoPPNon Twitter, Instagram, Facebook and LinkedIn

For further information please contact

Grnenthal

King's College London

Christopher Jansen

Communication Business Partner

Grnenthal GmbH

52099 Aachen

Phone: +49 241 569-1428

E-mail: Christopher.Jansen@grunenthal.com

Patrick O'Brien

Senior Media Officer

Insitute of Psychiatry, Psychology & Neuroscience King's College London

Phone: +44 07813 706 151

Email: Patrick.1.obrien@kcl.ac.uk

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Grnenthal and King's College London collaborate to develop human induced pluripotent stem cell-based microfluidic cultures for pain research - Yahoo...

Researchers reveal an ancient mechanism for wound repair – Science Daily

It's a dangerous world out there. From bacteria and viruses to accidents and injuries, threats surround us all the time. And nothing protects us more steadfastly than our skin. The barrier between inside and out, the body's largest organ is also its most seamless defense.

And yet the skin is not invincible. It suffers daily the slings and arrows of outrageous fortune, and it tries to keep us safe by sensing and responding to these harms. A primary method is the detection of a pathogen, which kicks the immune system into action. But new research from the lab of Rockefeller's Elaine Fuchs, published in Cell, reveals an alternative protective mechanism that responds to injury signals in wounded tissue -- including low oxygen levels from blood vessel disruption and scab formation -- and it doesn't need an infection to get into gear.

The study is the first to identify a damage response pathway that is distinct from but parallel to the classical pathway triggered by pathogens.

At the helm of the response is interleukin-24 (IL24), whose gene is induced in skin epithelial stem cells at the wound edge. Once unleashed, this secreted protein begins to marshal a variety of different cells to begin the complex process of healing.

"IL24 is predominately made by the wound-edge epidermal stem cells, but many cells of the skin -- the epithelial cells, the fibroblasts, and the endothelial cells -- express the IL24 receptor and respond to the signal. IL24 becomes an orchestrator that coordinates tissue repair," says Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development.

Hints from pathogen-induced signaling

Scientists have long understood how the host responses protect our body from pathogen-induced threats: somatic cells recognize invading bacteria or viruses as foreign entities and induce a number of defense mechanisms with the help of signaling proteins such as type 1 interferons.

But how does the body respond to an injury that may or may not involve foreign invader? If we cut a finger while slicing a cucumber, for example, we know it instantly -- there's blood and pain. And yet how the detection of injury leads to healing is poorly understood on a molecular basis.

While type 1 interferons rely on the signaling factors STAT1 and STAT2 to regulate the defense against pathogens, previous research by the Fuchs lab had shown that a similar transcription factor known as STAT3 makes its appearance during wound repair. Siqi Liu, co-first author in both studies, wanted to trace STAT3's pathway back to its origin.

IL24 stood out as a major upstream cytokine that induces STAT3 activation in the wounds.

Microbe-independent action

In collaboration with Daniel Mucida's lab at Rockefeller, the researchers worked with mice under germ-free conditions and found that the wound-induced IL24 signaling cascade is independent of germs.

But what injury signals induced the cascade? Wounds often extend into the skin dermis, where capillaries and blood vessels are located.

"We learned that the epidermal stem cells sense the hypoxic environment of the wound," says Yun Ha Hur, a research fellow in the lab and a co-first author on the paper.

When the blood vessels are severed and a scab forms, epidermal stem cells at the edge of the wound are starved of oxygen. This state of hypoxia is an alarm bell for cell health, and induced a positive feedback loop involving transcription factors HIF1a and STAT3 to amplify IL24 production at the wound edge. The result was a coordinated effort by a variety of cell types expressing the IL24 receptor to repair the wound by replacing damaged epithelial cells, healing broken capillaries, and generating fibroblasts for new skin cells.

Collaborating with Craig Thompson's group at Memorial Sloan Kettering Cancer Center, the researchers showed that they could regulate Il24 gene expression by changing oxygen levels.

Once the researchers pinpointed the origin of the tissue-repair pathway in epidermal stem cells, they studied the wound repair process in mice that had been genetically modified to lack IL24 functionality. Without this key protein, the healing process was sluggish and delayed, taking days longer than in normal mice to completely restore the skin.

They speculate that IL24 might be involved in the injury response in other body organs featuring epithelial layers, which act as a protective sheath. In recent studies, elevated IL24 activity has been spotted in epithelial lung tissue of patients with severe COVID-19 and in colonic tissue in patients with ulcerative colitis, a chronic inflammatory bowel disease.

"IL24 could be working as a cue to signal the need for injury repair in many organs," Hur says.

Linked by function and evolution

"Our findings provide insights into an important tissue damage sensing and repair signaling pathway that is independent of infections," explains Fuchs.

An analysis with evolutionary biologist Qian Cong at UT Southwestern Medical Center revealed that IL24 and its receptors share close sequence and structure homology with the interferon family. Though they may not always be working in coordination at every moment, IL24 and interferons are evolutionarily related and bind to receptors sitting near each other on the surface of cells. The researchers suspect that these signaling molecules derive from a common molecular pathway dating far back in our past.

"We think that hundreds of millions of years ago, this ancestor might have diverged into two pathways -- one being pathogen defense and the other being tissue injury," Liu says.

Perhaps the split occurred to cope with an explosion of pathogens and injuries that caused a sea of troubles for life on Earth.

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Researchers reveal an ancient mechanism for wound repair - Science Daily

The gene-therapy revolution risks stalling if we don’t talk about drug … – Nature.com

A gene-editing therapy to correct deformed red blood cells in sickle-cell disease is in the works but at what cost?Credit: Eric Grave/SPL

We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.), wrote James Watson and Francis Crick in this journal in 1953 (J. D. Watson and F. H. C. Crick Nature 171, 737738; 1953). This structure has novel features which are of considerable biological interest.

In the 70 years since those famous words were published, researchers have poured huge effort into unravelling those features and harnessing them for medicine. The result is a flourishing understanding of the genetic causes of diseases and a host of therapies designed to treat them.

Seventy years from now, the world might look back on 2023 as a landmark, as well. This year could see the first authorization of a therapy based on CRISPRCas9 gene editing, that involves tweaking the DNA in the bodys non-reproductive (somatic) cells. Gene editing allows scientists and could soon permit clinicians to make changes to targeted regions in the genome, potentially correcting genes that cause disease. Regulators in the United States, the European Union and the United Kingdom are evaluating a therapy that uses this approach to treat sickle-cell disease, and a decision could be made in the next few months.

CRISPR gene therapy shows promise against blood diseases

But even as such advances accrue, researchers are worrying about the future role of gene editing as well as other, more established forms of gene therapy in treating disease. Gene therapies currently carry eye-watering price tags, putting them out of the reach of many who need them. High prices could diminish the willingness of government funders to pay for gene-therapy research. And that, in turn, would make it harder for research institutions to continue to attract top talent to the field. Researchers, especially health economists, must work urgently with industry and governments to find a more affordable funding model.

CRISPRCas9s speedy path to the clinic was paved by years of steady advances in forms of gene therapy that use a virus to shuttle genes into cells. Over the past decade, regulators have approved several such gene therapies, for example CAR-T-cell therapies, which engineer immune cells to treat cancer. Hundreds more are in clinical trials.

These therapies typically cost something like US$1 million for a single treatment, and more once the costs of administering them, such as hospital stays and procedures required to isolate and manipulate cells, are factored in. Last year, the US Food and Drug Administration approved the first gene therapy to treat haemophilia B, a genetic disease that impairs blood clotting. The price is $3.5 million per treatment, making the therapy, called Hemgenix, the most expensive drug in the world.

Gene therapies are more costly to develop and produce than are more well-established treatments based on small-molecule drugs. But gene therapies can also carry the hope of a cure, freeing recipients from both long-term reliance on expensive medicines and the risk of hospitalizations. Some have argued that this justifies the high cost: if a therapy can save millions in downstream treatments, the initial outlay would still save money overall. Over time, after all, the costs of more-conventional treatments add up: one study, for example, found that in the United States, the cost of treating a person with sickle-cell anaemia until the age of 64 is $1.7 million (K. M. Johnson et al. Blood Adv. 7, 365374; 2023).

Researchers welcome $3.5-million haemophilia gene therapy but questions remain

Even in wealthy countries, health-care systems are ill-equipped to shoulder the high initial costs associated with gene therapies. In 2021, therapeutics developer Bluebird Bio in Somerville, Massachusetts, withdrew plans to market a gene therapy for -thalassaemia another blood disorder in Europe, after failing to reach an agreement with European authorities over the price. It said it would focus its sales efforts on the United States, where there has been comparatively little regulation of drug costs.

But even in the United States, costs matter. US health insurance is often subsidized by employers, and some are already saying that they will probably restrict their coverage of gene therapies in the next year, says Steven Pearson, president of the Institute for Clinical and Economic Review, a health-economics think tank in Boston, Massachusetts.

Low- and middle-income countries, meanwhile, are left entirely in the lurch. This is especially painful given that some of the diseases under consideration, such as -thalassaemia and sickle-cell disease, are more common in poorer parts of the world than in wealthy nations. In some sub-Saharan regions, for example, it is estimated that about 2% of children are born with sickle-cell disease. This is likely to be an underestimate, given how little screening is taking place.

It is too soon to know how much the CRISPRCas9 treatment for sickle-cell disease would cost; neither of its developers, Vertex Pharmaceuticals in Boston, Massachusetts, or CRISPR Therapeutics in Cambridge, Massachusetts, have disclosed what they will charge. But researchers are bracing themselves for the price tag to come.

At the Third International Summit on Human Genome Editing, held in London in March, much of the discussion centred on making gene-editing therapies accessible, particularly to low- and middle-income countries. The focus was on technological approaches to streamline the production and testing of such treatments. The sickle-cell treatment, for example, requires clinicians to isolate and edit blood-forming stem cells, destroy those that remain in the body, and then reinfuse the edited cells. Converting this to a genome-editing procedure that could be performed directly in the body rather than in isolated cells could make the treatment cheaper and more accessible.

Expensive treatments for genetic disorders are arriving. But who should foot the bill?

Another appealing approach is to develop gene-therapy platforms that have already been confirmed to be safe and effective. Gene-therapy developers could then just swap in a gene that targets the chosen disease, without the gamut of tests of safety and efficacy that are required when starting from scratch.

But technological solutions such as these will go only so far. US drug pricing has little to do with how much it costs to produce a therapy, says Pearson, because companies can charge as much as the market will bear. How much that price will drop in other countries could be limited by intellectual property rights and hindered by the complexities of making generic copies of biological drugs such as gene therapies. Some academic centres are trying to develop and deploy gene therapies without relying on pharmaceutical companies, but it is unclear how far such efforts can stretch without the financial resources and regulatory expertise found in industry.

In addition to pricing, gene-therapy technologies are mired in debates around regulation and intellectual property. How each of these plays out will determine how far researchers can go in capitalizing on Watson and Cricks initial discovery. Its important that scientists have an active role in these debates, and that they push such discussions to the fore sooner rather than later.

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The gene-therapy revolution risks stalling if we don't talk about drug ... - Nature.com

Research Identifies New Target Which May Prevent Blood Cancer – Cannon Courier

An international coalition of biomedical researchers co-led by Alexander Bick, MD, PhD, at Vanderbilt University Medical Center has determined a new way to measure the growth rate of precancerous clones of blood stem cells that one day could help doctors lower their patients' risk of blood cancer.

The technique, called PACER, led to the identification of a gene that, when activated, drives clonal expansion. The findings, published in the journal Nature, suggest that drugs targeting this gene, TCL1A, may be able to suppress clonal growth and associated cancers.

"We think that TCL1A is a new important drug target for preventing blood cancer," said Bick, the study's co-corresponding author with Stanford University's Siddhartha Jaiswal, MD, PhD.

More than 10% of older adults develop somatic (non-inherited) mutations in blood stem cells that can trigger explosive, clonal expansions of abnormal cells, increasing the risk for blood cancer and cardiovascular disease.

Since arriving at VUMC in 2020, Bick, assistant professor of Medicine in the Division of Genetic Medicine and director of the Vanderbilt Genomics and Therapeutics Clinic, has contributed to more than 30 scientific papers that are revealing the mysteries of clonal growth (hematopoiesis).

With age, dividing cells in the body acquire mutations. Most of these mutations are innocuous "passenger" mutations. But sometimes, a mutation occurs that drives the development of a clone and ultimately causes cancer.

Prior to this study, scientists would measure clonal growth rate by comparing blood samples taken decades apart. Bick and his colleagues figured out a way to determine the growth rate from a single timepoint, by counting the number of passenger mutations.

"You can think of passenger mutations like rings on a tree," Bick said. "The more rings a tree has, the older it is. If we know how old the clone is (how long ago it was born) and how big it is (what percentage of blood it takes up), we can estimate the growth rate."

The PACER technique for determining the "passenger-approximated clonal expansion rate" was applied to more than 5,000 individuals who had acquired specific, cancer-associated driver mutations in their blood stem cells, called "clonal hematopoiesis of indeterminate potential" or CHIP, but who did not have blood cancer.

Using a genome-wide association study, the investigators then looked for genetic variations that were associated with different clonal growth rates. To their surprise, they discovered that TCL1A, a gene which had not previously been implicated in blood stem cell biology, was a major driver of clonal expansion when activated.

The researchers also found that a commonly inherited variant of the TCL1A promoter, the DNA region which normally initiates transcription (and thus activation) of the gene, was associated with a slower clonal expansion rate and a markedly reduced prevalence of several driver mutations in CHIP, the second step in the development of blood cancer.

Experimental studies demonstrated that the variant suppresses gene activation.

"Some people have a mutation that prevents TCL1A from being turned on, which protects them from both faster clone growth and from blood cancer," Bick said. That's what makes the gene so interesting as a potential drug target.

The research is continuing with the hope of identifying additional important pathways relevant to precancerous growth in other tissues as well as blood, he added.

Researchers from more than 50 institutions across the United States, as well as Germany, Sweden, and the Netherlands participated in the study. Other VUMC co-authors were Taralyn Mack, Benjamin Shoemaker, MD, MSCI, and Dan Roden, MD.

The research at VUMC is supported by National Institutes of Health grant OD029586, a Burroughs Wellcome Fund Career Award for Medical Scientists, the E.P. Evans Foundation & RUNX1 Research Program, a Pew-Stewart Scholar for Cancer Research Award, the VUMC Brock Family Endowment, and a Young Ambassador Award from the Vanderbilt-Ingram Cancer Center.

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Research Identifies New Target Which May Prevent Blood Cancer - Cannon Courier

Apoptotic cell death in diseaseCurrent understanding of the … – Nature.com

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