Category Archives: Cell Medicine

LONDON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) today announced that SYMDEKO (tezacaftor/ivacaftor and ivacaftor) is reimbursed in Australia for people with cystic fibrosis (CF) ages 12 years and older who are homozygous for the F508del mutation or who have one copy of the F508del mutation and another responsive residual function (RF) mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. People with CF who have one copy of the F508del mutation and another responsive RF mutation in the CFTR gene will have access to a medicine for the cause of their CF for the first time. In addition, ORKAMBI (lumacaftor/ivacaftor) is now also reimbursed for the treatment of children with CF ages 2 to 5 who have two copies of the F508del mutation in the CFTR gene. Patients over the age of 6 have already been able to access ORKAMBI in Australia since October 2018.

Following previously received positive recommendations from the Pharmaceutical Benefits Advisory Committee (PBAC), eligible patients in Australia will be able to access both medicines immediately, and the medicines will be listed on the Pharmaceutical Benefits Scheme (PBS) from December 1st.

We are pleased that SYMDEKO and ORKAMBI will be made available immediately to eligible cystic fibrosis patients in Australia. We appreciate that the PBAC has recognized the value of these medicines to patients and thank the Department of Health and the Minister for Health in Australia for their strong engagement and collaboration to finalize the agreement, said Ludovic Fenaux, Senior Vice President, Vertex International.

Vertexs CF medicines are reimbursed in 17 countries around the world including Austria, Denmark, Germany, the Republic of Ireland, Italy, the Netherlands, Sweden and the U.S.

About CFCystic Fibrosis (CF) is a rare, life-shortening genetic disease affecting approximately 75,000 people worldwide. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF. While there are many different types of CFTR mutations that can cause the disease, the vast majority of all people with CF have at least one F508del mutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

About SYMDEKO (tezacaftor/ivacaftor) in combination with ivacaftorSome mutations result in CFTR protein that is not processed or folded normally within the cell, and that generally does not reach the cell surface. Tezacaftor is designed to address the trafficking and processing defect of the CFTR protein to enable it to reach the cell surface and ivacaftor is designed to enhance the function of the CFTR protein once it reaches the cell surface.

Mutations in the CFTR gene, responsive to SYMDEKO, that are currently registered in Australia include F508del/f and P67L, R117C, L206W, R352Q, A455E, D579G, 711+3AG, S945L, S977F, R1070W, D1152H, 2789+5GA, 3272-26AG, 3849+10kbCT, E56K, R74W, D110E, D110H, E193K, E831X, F1052V, K1060T, A1067T, F1074L and D1270N.

About ORKAMBI (lumacaftor/ivacaftor) and the F508del mutationIn people with two copies of the F508del mutation, the CFTR protein is not processed and trafficked normally within the cell, resulting in little-to-no CFTR protein at the cell surface. Patients with two copies of the F508del mutation are easily identified by a simple genetic test. Lumacaftor/ivacaftor is a combination of lumacaftor, which is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del-CFTR protein, and ivacaftor, which is designed to enhance the function of the CFTR protein once it reaches the cell surface.

About VertexVertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has three approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational medicines in other serious diseases where it has deep insight into causal human biology, such as sickle cell disease, beta thalassemia, pain, alpha-1 antitrypsin deficiency, Duchenne muscular dystrophy and APOL1-mediated kidney diseases.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London, UK. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including nine consecutive years on Science magazine's Top Employers list and top five on the 2019 Best Employers for Diversity list by Forbes.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, the statements in the second and third paragraphs of the press release. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under Risk Factors in Vertex's annual report and subsequent quarterly reports filed with the Securities and Exchange Commission and available through the company's website at http://www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

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Newswise Bioengineers at the University of California San Diego are a step closer to making CAR T-cell therapy safer, more precise and easy to control. They developed a system that allows them to select where and when CAR T cells get turned on so that they destroy cancer cells without harming normal cells.

The system requires two keysthe drug Tamoxifen and blue lightto activate CAR T cells to bind to their targets. Just one key keeps the cells inactive. Researchers tested their system on live cell cultures as a proof of concept. Their next step is to do tests on tumors in mice.

With our technology, we can have better control over CAR T-cell treatments in patients and potentially avoid non-specific targeting of organs and nonmalignant tissues, said UC San Diego bioengineering professor Peter Yingxiao Wang, a co-senior author of the study. Researchers recently published their work in ACS Synthetic Biology.

Chimeric antigen receptor (CAR) T-cell therapy is a promising new approach to treat cancer. It involves collecting a patients T cells and genetically engineering them to express special receptors on their surface that can recognize an antigen on targeted cancer cells. The engineered T cells are then infused back into the patient to find and attack cells that have the targeted antigen on their surface.

This approach has worked well for some types of blood cancer and lymphoma. But a major problem, Wang explains, is that it can work too well. Many targeted cancer antigens are also expressed on healthy cells, which can lead to attack of essential organs such as the heart, lungs or liver. This risk is known as on-target, off-tumor toxicity and can be life-threatening to patients receiving CAR T-cell therapy.

Traditional CAR T cells are always on, meaning they continuously express an antigen-targeting receptor. Our approach was to engineer T cells that can be selectively turned on to express the receptor at a specific location and time frame, Wang said.

Wang and colleagues engineered T cells that are only activated following a sequence of two inputs: treatment with the small molecule drug Tamoxifen, followed by exposure to short pulses of low intensity blue light. The chance to have accidental activation will be extremely low because you need both inputs at the same time. The drug primes the cells, and the light allows us to precisely guide where they get activated, Wang said.

Initially, the CAR T cells are in standby mode. In order to turn on, two particular proteins (one outside the nucleus and one inside) need to bind together in order to trigger expression of the antigen-targeting receptor. The drug Tamoxifen first binds to one of these proteins and helps it move into the nucleus, where the other protein awaits. Blue light then induces both proteins to combine. Any cells treated with the drug but not exposed to blue light remain in standby mode.

The light cannot penetrate deeply in the body, so Wang envisions that this approach could be useful for treating cancers on the skin, head and neck. He is now looking to collaborate with clinicians to do in vivo testing to treat melanoma.

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Paper title: An AND-gated drug and photoactivatable Cre-loxP system for spatiotemporal control in cell-based therapeutics. Co-authors include Molly E. Allen, Jeyan Thangaraj, Philip Kyriakakis, Yiqian Wu, Ziliang Huang, Phuong Ho, Yijia Pan, Praopim Limsakul and Xiangdong Xu, UC San Diego; and Wei Zhou, Chongqing Cancer Hospital, China.

This work was supported by grants from the National Institutes of Health, the Galvanizing Engineering in Medicine program under the Institute of Engineering in Medicine and Altman Clinical and Translational Research Institute (ACTRI) at UC San Diego, the American Cancer Society, and the National Heart, Lung, and Blood Institute (NHLBI).

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While many people love colorful photos of landscapes, flowers or rainbows, some biomedical researchers treasure vivid images on a much smaller scale as tiny as one-thousandth the width of a human hair.

To study the micro world and help advance medical knowledge and treatments, these scientists use fluorescent nano-sized particles.

Quantum dots are one type of nanoparticle, more commonly known for their use in TV screens. Theyre super tiny crystals that can transport electrons. When UV light hits these semiconducting particles, they can emit light of various colors.

That fluorescence allows scientists to use them to study hidden or otherwise cryptic parts of cells, organs and other structures.

Im part of a group of nanotechnology and neuroscience researchers at the University of Washington investigating how quantum dots behave in the brain.

Common brain diseases are estimated to cost the U.S. nearly US$800 billion annually. These diseases including Alzheimers disease and neurodevelopmental disorders are hard to diagnose or treat.

Nanoscale tools, such as quantum dots, that can capture the nuance in complicated cell activities hold promise as brain-imaging tools or drug delivery carriers for the brain. But because there are many reasons to be concerned about their use in medicine, mainly related to health and safety, its important to figure out more about how they work in biological systems.

Researchers first discovered quantum dots in the 1980s. These tiny particles are different from other crystals in that they can produce different colors depending on their size. They are so small that that they are sometimes called zero-dimensional or artificial atoms.

The most commonly known use of quantum dots nowadays may be TV screens. Samsung launched their QLED TVs in 2015, and a few other companies followed not long after. But scientists have been eyeing quantum dots for almost a decade. Because of their unique optical properties they can produce thousands of bright, sharp fluorescent colors scientists started using them as optical sensors or imaging probes, particularly in medical research.

Scientists have long used various dyes to tag cells, organs and other tissues to view the inner workings of the body, whether that be for diagnosis or for fundamental research.

The most common dyes have some significant problems. For one, their color often cannot survive very long in cells or tissues. They may fade in a matter of seconds or minutes. For some types of research, such as tracking cell behaviors or delivering drugs in the body, these organic dyes simply do not last long enough.

Quantum dots would solve those problems. They are very bright and fade very slowly. Their color can still stand out after a month. Moreover, they are too small to physically affect the movement of cells or molecules.

Those properties make quantum dots popular in medical research. Nowadays quantum dots are mainly used for high resolution 3D imaging of cells or molecules, or real-time tracking probes inside or outside of animal bodies that can last for an extended period.

But their use is still restricted to animal research, because scientists are concerned about their use in human beings. Quantum dots commonly contain cadmium, a heavy metal that is highly poisonous and carcinogenic. They may leak the toxic metal or form an unstable aggregate, causing cell death and inflammation. Some organs may tolerate a small amount of this, but the brain cannot withstand such injury.

My colleagues and I believe an important first step toward wider use of quantum dots in medicine is understanding how they behave in biological environments. That could help scientists design quantum dots suitable for medical research and diagnostics: When theyre injected into the body, they need to stay small particles, be not very toxic and able to target specific types of cells.

We looked at the stability, toxicity and cellular interactions of quantum dots in the developing brains of rats. We wrapped the tiny quantum dots in different chemical coats. Scientists believe these coats, with their various chemical properties, control the way quantum dots interact with the biological environment that surrounds them. Then we evaluated how quantum dots performed in three commonly used brain-related models: cell cultures, rat brain slices and individual live rats.

We found that different chemical coats give quantum dots different behaviors. Quantum dots with a polymer coat of polyethylene glycol (PEG) were the most promising. They are more stable and less toxic in the rat brain, and at a certain dose dont kill cells. It turns out that PEG-coated quantum dots activate a biological pathway that ramps up the production of a molecule that detoxifies metal. Its a protective mechanism embedded in the cells that happens to ward off injury by quantum dots.

Quantum dots are also eaten by microglia, the brains inner immune cells. These cells regulate inflammation in the brain and are involved in multiple brain disorders. Quantum dots are then transported to the microglias lysosomes, the cells garbage cans, for degradation.

But we also discovered that the behaviors of quantum dots vary slightly between cell cultures, brain slices and living animals. The simplified models may demonstrate how a part of the brain responds, but they are not a substitute for the entire organ.

For example, cell cultures contain brain cells but lack the connected cellular networks that tissues have. Brain slices have more structure than cell cultures, but they also lack the full organs blood-brain barrier its Great Wall that prevents foreign objects from entering.

Our results offer a warning: Nanomedicine research in the brain makes no sense without carefully considering the organs complexity.

That said, we think our findings can help researchers design quantum dots that are more suitable for use in living brains. For example, our research shows that PEG-coated quantum dots remain stable and relatively nontoxic in living brain tissue while having great imaging performance. We imagine they could be used to track real-time movements of viruses or cells in the brain.

In the future, along with MRI or CT scans, quantum dots may become vital imaging tools. They might also be used as traceable carriers that deliver drugs to specific cells. Ultimately, though, for quantum dots to realize their biomedical potential beyond research, scientists must address health and safety concerns.

Although theres a long way to go, my colleagues and I hope the future for quantum dots may be as bright and colorful as the artificial atoms themselves.

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Burn specialists at Massachusetts General Hospital are the first in the world to successfully use live-cell, genetically engineered pig skin to temporarily close a burn wound in a human patient but the breakthrough has drawn opposition from People for the Ethical Treatment of Animals.

The ultimate holy grail is the end to the worlds organ shortage, that would be the holy grail, this has come at a time when genetic editing is really hot and what we could do in years, we can do in weeks, said Dr. Jeremy Goverman of the MGH Sumner Redstone Burn Service.

The pig tissue, known as xenoskin, was transplanted directly onto a human burn wound next to a larger piece of human skin.

Five days later, surgeons removed the human skin and the pig tissue to see that both grafts were stuck to the wound bed and were indistinguishable from each other.

Following the procedure, the burn wound was then treated further with a skin graft taken from the patients thigh. Healing progressed well and the patient will return to work soon.

The goal is to replace skin with xenoskin thats like it enough that it doesnt get rejected, said Goverman. Down the line we hope to ultimately create something thats not temporary.

The biggest push now is actually decreasing your donor site size and decreasing how much skin you have to harvest, said Goverman.

Patients who receive this type of graft typically have severe burns that require more than one operation and about a week of hospitalization.

Weve been using dressing like this in the past, we just havent been able to use anything with live cells. The live cells have all the appropriate factors that could really stimulate and regenerate and close our wounds for us, said Goverman.

MGH worked with Boston-based XenoTherapeutics, which designed the safety protocols for the special live-pig tissue graft.

Paul Holzer, CEO of XenoTherapeutics said, We have taken a small but unprecedented step in bringing xenotransplantation from theory to therapy, one that we hope will advance this promising field of medicine and benefit patients around the world.

Human skin grafts are subject to a national shortage and can be expensive, therefore using the pig skin can serve as a viable alternative, according to MGH.

But Alka Chandna, vice president of laboratory investigations cases at PETA, said, Its categorically unethical to steal organs from another sentient being whos still using them. Pigs are individuals, not warehouses for spare parts, said Chandna.

Chandna said, Tinkering with the genes of these intelligent, sensitive beings to turn them into organ factories is a waste of lives, time and money and the suffering caused is unimaginable.

The advancement of the procedure reaches back decades to genetically modified pigs that were developed in the 1990s at MGH by Dr. David Sachs.

The modifications removed a gene specific to pigs and not present in humans, allowing the pig skin to appear less foreign to the human immune system.

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Cambridge, UK-based biotech startup Mogrify, which is working on systematizing the development of novel cell therapies in areas such as regenerative medicine, has closed an initial $16 million Series A.

The raise follows a $4M seed in February taking its total raised to date to $20M.

Put simply, Mogrifys approach entails analysis of vast amounts of genomic data in order to identify the specific energetic changes needed to flip an adult cell from one type to another without having to reset it to a stem cell state with huge potential utility for a wide variety of therapeutic use-cases.

What were trying to do with Mogrify is systematize that process where you can say heres my source cell, heres my target cell, here are the differences between the networks and here are the most likely points of intervention that were going to have to make to drive the fate of an adult cell to another adult cell without going through a stem cell stage, says CEO and investor Dr Darrin Disley.

So far he says its successfully converted 15 cells out of 15 tries.

Were now rapidly moving those on through our own programs and partnership programs, he adds.

Mogrifys business has three main components: Internal program development of cell therapies (current cell therapies its developing include enhancing augmented cartilage implantation; non-invasive treatment of ocular damage; and for blood disorders). Its also developing a universal source of cells for use in immunotherapy to act as disease-eaters, asDisley puts it.

Speculative IP development is another focus. Because of the systematic nature of the technology were in a position very rapidly to identify areas of therapy that have particular cell conversions at their essence and then drive that IP generation around those cells very quickly and create an IP footprint, he says.

Partnering deals is the third piece. Mogrify is also working with others to co-develop and bring targeted cell therapies to market. Disley says its already closed some partnerships, though its not announcing any names yet.

The startup is drawing on around a decades worth of recent work genomics science. And specifically on a data-set generated by an international research effort, called Fantom 5, which its founders had early access to.

We started with that massive Fantom data-set. Thats the baseline, the background if you like. Think of it like two cities in America: Chicago and New York. Theres your source cell, theres your target cell. And because you have all the background data of every piece of the network every building, every skyscraper if you look at the two you can identify the difference in the gene expression, therefore you can identify which factors will regulate a wide array of those genes. So you can start identifying the differences between the two, explainsDisley.

Weve then added to that massive data sets in DNA-protein and protein-protein interactions so you start to now overlay all of that data. And then weve added on top of that new next-gen sequencing data and epigenetic data. So youve now got this massive data-set. Its like having a network map between all the different cell types. So youre therefore then able to make predictions on how many interventions, what interventions are needed to drive that change of state and its systematic. It doesnt just recommend one set. Theres a ranking. It can go down to hundreds. And there is some overlap and redundancies, so for example if one youre preferred thing doesnt work the way you wanted it to you can go back and select another.

Or if theres an IP issue around that factor you can ignore that piece of the network and use an alternative route. And once youve got to your target cell, if it needs to some tweaking you can actually re-sequence it and take that back and thats your starting cell again. And you can go through this optimization process. So what comes out at the other end youve got a patent that it like a small molecule composition of matter patent; its the therapeutic. So youre not coming out with the target, youre actually coming out with here is the composition of matter on the cell.

In terms of timeframe for getting novel cell therapies from concept to market Disley suggests a range of between four and seven years.

Once youve identified the cell type that can be be the basis of your GMP manufacturable process and then you can tweak that to take it to the therapeutic indication you can develop a cell therapy and bring that to market in five years, he says. Its not like the old days with small molecules where it can take ten, 15, 20 years to get a serious therapy on the market.

When youre treating patients is because there are no other treatments for them, when you go into phase two and do your safety study [and] efficacy study youre actually treating patients already in terms of their disease. And if you get it right you can get a fast track approval. Or a conditional approval so that you may not even have to do a phase 3 [testing].

Were not using any artificial intelligence here, he also emphasizes, pointing to his experience investing in companies in the big extreme data space which he argues do best by using unbiased approaches.

AI I think is still trying to find its way, he continues. Because in its essence it will be able to get to answers with smaller amounts of data but its only as good as the data you train it on. And the danger with AI it just learns to recognize what you want it to recognize. It doesnt know what it doesnt know.

In combination, once you continue to generate this massive cell network data etc you can start applying aspects of machine learning and AI. But you couldnt do Mogrify with AI without the data. You have to do it that way. And the data is so complex and combinatorial 2,000 transcription factors, in terms of regulation of those genes, they then interact in network to do the protein-protein interactions, youve got epigenetic aspects of that, you could even start adding cell microbiome effects to that later so youve got a lot of factors that could influence the phenotype of the cell thats coming out the other end.

So I think with AI you have to be a little careful. I think it will be a more optimizing tool once youve got sufficient confidence in your system.

The plan for the Series A funding is to ramp up Mogrifys corporate operations and headcount including bringing in senior executives and expertise from industry as well as spending to fund its therapy development programs.

Disley notes its recent appointment of Dr Jane Osbourn as chair as one example.

Were bringing in more people with a lot of cell therapy experience from big pharma, around then more on the manufacturing and delivery of that so really building so that were not just a tech company, he says. Weve very strong already, were already 35 people on the tech and early stage drug discovery side were going to add another 30 to that. But thats going to be increasingly more people with big pharma, cell therapy development, manufacturing experience to get products on to market.

Partner search is another focus for the Series A. Were trying to find the right strategy partners. Were not doing services, were not doing products so we want to find the right strategic partners in terms of doing multi-programs in a partnership, he adds. And then a series of more tactical deals where people have got a specific problem with a cell conversion. These more turnkey deals, if you like. We still get up-fronts, milestones and royalties but theyre smaller.

Despite now having enough money for the next two to two and half years its also leaving the Series A open to continue expanding the round over the next 12 months up to a maximum of another $16M.

We have so many interested investors, Disley tells us. This round we didnt actually open our round. We did it with internal investors and people were very close to who weve worked with before, and there were investors lining up [so] we are leaving it open so that in these next 12 months we may choose to increase the amount we bring in.

It would be a maximum of another $16M if it was an A round but we may decide just to go straight forward if we progress very fast to a much bigger B round.

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UK biotech startup Mogrify injects $16M to get novel cell therapies to market soon - TechCrunch

Jibran Sualeh Muhammad, Manju Nidagodu Jayakumar, Noha Mousaad Elemam, Thenmozhi Venkatachalam, Tom Kalathil Raju, Rifat Akram Hamoudi, Azzam A Maghazachi

College of Medicine, and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates

Correspondence: Azzam A MaghazachiDepartment of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab EmiratesEmail amaghazachi@sharjah.ac.ae

Introduction: Although natural killer (NK) are major cells used to treat cancer patients, recent clinical trials showed that NK92 cells can be also used for the same purpose due to their high anti-tumor activity. Here, we examined whether these cells might be inflammatory due to the release of interleukin-1 (IL-1), and whether the anti-inflammatory molecules dimethyl fumarate (DMF), or monomethyl fumarate (MMF) impair this activity.Methods: NK92 cells were examined for the synthesis and release of IL-1 utilizing RT-PCR and ELISA assay, respectively. The expression of hydroxy-carboxylic acid receptors (HCA)1, HCA2 and HCA3 was detected by immunoblotting, flow cytometry, immunofluorescence and RT-PCR assays. The activation of caspase-1 and Gasdermin D (GSDMD) was evaluated by immunoblot assay. Pyroptosis was demonstrated by immunofluorescence imaging. Expression of DNA methyltransferases (DNMTs) mRNA was determined by whole transcriptome and immunoblot analyses.Results: LPS-induced the release of IL-1 from NK92 cells, whereas DMF or MMF inhibited this induction. The effect of these drugs was due to inhibiting the conversion of procaspase-1 into active caspase-1. NK92 cells highly expressed GSDMD, a pyroptotic-mediated molecule. However, LPS induced the distribution of GSDMD into the cell membranes, corroborated with the presence of pyroptotic bodies, an activity that was inhibited by DMF or MMF. These molecule also inhibited the generation of GSDMD through DNMT-mediated hypermethylation of the promoter region of GSDMD gene. These results were supported by increased expression of DNMTs mRNA as determined by whole transcriptome analysis.Discussion: Our results are the first to show that NK92 cells utilize GSDMD pathway to release IL-1. Further, DMF and MMF which were previously shown to enhance NK cell cytotoxicity, also inhibit the inflammatory effects of these cells, making them most suitable for treating cancer patients.

Keywords: pyroptosis, gasdermin D, NK cells, IL-1, dimethyl fumarate, monomethyl fumarate

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Gasdermin D Hypermethylation Inhibits Pyroptosis And LPS-Induced IL-1b | ITT - Dove Medical Press

The San Diego Zoos project to save the northern white rhino is now researching how to make sperm and egg cells to help resurrect the nearly extinct species, a zoo scientist said Thursday.

Marisa Korody, a conservation genetics scientist at the zoos Institute for Conservation research, gave the update to a scientific audience at the Sanford Consortium for Regenerative Medicine in La Jolla.

ICR scientists have developed induced pluripotent stem cells from frozen tissue samples, Korody said. These cells act like embryonic stem cells. In theory, they can be converted into nearly any cell type in the body.

A number of tests have confirmed that these are true pluripotent stem cells, she said, displaying a video of beating heart cells, or cardiomyocytes, made from the cells.

In theory, sperm and egg cells can be united to produce embryos, which can be implanted into closely related southern white rhino females, serving as surrogate mothers. Six of these are now being trained at the San Diego Zoo Safari Park.

But making these gametes is complicated, she said. They require supporting structures to mature properly, and nobody knows how to determine if they do mature properly. This means the zoo and colleagues are performing original science.

So-called primordial germ cells, the common ancestor of eggs and sperm, have arisen spontaneously. But they need to be reliably generated under controlled circumstances.

All rhino species and subspecies are endangered due to habitat loss and poaching for their horns, Korody said. Its our fault, we really need to help these species, she said.

On the positive side, Korody said the dozen or so tissue samples from northern white rhinos contains enough genetic diversity to bring back a viable population.

This is known because that diversity is greater than that in the southern white rhino, which rebounded from near-extinction to a population of about 18,000.

A long-discussed state initiative to refund Californias stem cell program with $5.5 billion has at last begun.

Backers filed the initiative Thursday, according to the California Stem Cell Report, which closely tracks the program, called the California Institute for Regenerative Medicine, or CIRM. If it gets 633,212 valid signatures, the initiative will appear on the November 2020 ballot.

CIRM was founded by the passage of Proposition 71 in 2004. It got $3 billion from the sale of state bonds. It has been severely criticized for overpromising the speed at which stem cell treatments would get to patients. Advocates said the agency has had to go slow because of safety reasons.

Theres also the question of whether the agency should get more money, or whether its work should be transferred to private entities. California has the biggest biomedical industry in the nation, but it also has billions in state liabilities for purposes such as pensions. Critics say the state needs to address these unfunded liabilities.

Robert N. Klein, a real estate investment banker who led the original campaign to create CIRM, said in a recent interview that the new funding was necessary to ensure that therapies now in the clinic can reach patients.

The initiative sets aside $1.5 billion for research and development of treatments for neurological conditions, such as Alzheimers disease, Parkinsons disease, and stroke. It also provides money to help disadvantaged patients receive these treatments, Klein said.

Patients who live far away from major academic centers may have difficulty arranging to stay nearby while awaiting or receiving treatment, Klein said.

Initiative supporters need to convince the public that the $5.5 billion from state bonds is a wise use of public money. Earlier this week, a study from University of Southern California professors said that it was.

CIRM, funded with $3 billion from state bonds, has yielded $10.7 billion of additional gross output, or sales revenue, the study said. In addition, more than 56,000 full-time jobs were created. Go to http://j.mp/cirmeireport for the study.

The agency said the study and another report were funded by $206,000 from CIRM, which said the study was independent.

However, the California Stem Cell Report said the study didnt convince critics of the agency, who said the agency has received enough money as it is.

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Saving rhinos with stem cells; $5.5 billion stem cell ballot measure readied - The San Diego Union-Tribune

The 2019 Nobel Prize in Medicine awarded for research in cellular responses to oxygen By Benjamin Mateus 10 October 2019

In the course of a lifetime, the human heart will beat more than three billion times. We will have taken more than 670 million breaths before we reach the end of our lives. Yet, these critical events remain unconscious and imperceptible in everyday life, unless we exert ourselves, such as running up several flights of stairs. We quickly tire, stop to take deep breaths and become flushed.

With the deepening comprehension by medical science of how our bodies work, we have come to better understand the fundamental importance of oxygen to life. Every living organism relies on it in one form or another. However, how cells and tissues can monitor and respond to oxygen levels remained difficult to elucidate. It has only been late in the 20th century with advances in cellular biology and scientific instrumentation that these processes have finally been explained.

On Monday, the 2019 Nobel Prize in Physiology or Medicine was awarded jointly to three individuals: William G. Kaelin, Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza. Specifically, their discoveries helped elucidate the mechanisms for lifes most basic physiologic processes.

They were able to discover how oxygen levels directly affect cellular metabolism, which ultimately controls physiological functions. More importantly, their findings have significant implications for the treatments of conditions as varied as chronic low blood counts, kidney disease, patients with heart attacks or stroke and cancers. One of the hallmarks of cancer is its ability to generate new blood vessels to help sustain its growth. It also uses these oxygen cellular mechanisms to survive in low oxygen environments.

Dr. William G. Kaelin Jr. is a professor of medicine at Harvard University and the Dana-Farber Cancer Institute. The main focus of his work is on studying how mutations in what are called tumor suppressor genes lead to cancer development. Tumor suppressor genes are special segments of the DNA whose function is to check the integrity of the DNA before allowing a copy of itself to be made and undergo cell division, which prevents cells from propagating errors. Cellular mechanisms are then recruited to fix these errors or drive the cell to destroy itself if the damage is too severe or irreparable.

His interest in a rare genetic disorder called Von Hippel-Lindau disease (VHL) led him to discover that cancer cells that lacked the VHL gene expressed abnormally high levels of hypoxia-regulated genes. The protein called the Hypoxia-Inducible Factor (HIF) complex was first discovered in 1995 by Gregg L. Semenza, a co-recipient of the Nobel Prize. This complex is nearly ubiquitous to all oxygen-breathing species.

The function of the HIF complex in a condition of low oxygen concentration is to keep cells from dividing and growing, placing them in a state of rest. However, it also signals the formation of blood vessels, which is important in wound healing as well as promoting the growth of blood vessels in developing embryos. In cancer cells, the HIF complex helps stimulate a process called angiogenesis, the formation of new blood vessels, which allows the cancer cells to access nutrition and process their metabolic waste, aiding in their growth. When the VHL gene is reintroduced back into the cancer cells, the activity of the hypoxia-regulated genes returns to normal.

Dr. Gregg L. Semenza is the founding director of the vascular program at the Johns Hopkins Institute for Cell Engineering. He completed his residency in pediatrics at Duke University Hospital and followed this with a postdoctoral fellowship at Johns Hopkins. His research in biologic adaptations to low oxygen levels led him to study how the production of erythropoietin (EPO) was controlled by oxygen. EPO is a hormone secreted by our kidneys in response to anemia. The secretion of EPO signals our bone marrow to produce more red blood cells.

His cellular and mouse model studies identified a specific DNA segment located next to the EPO gene that seemed to mediate the production of EPO under conditions of low oxygen concentration. He called this DNA segment HIF.

Sir Peter J. Ratcliffe, a physician and scientist, trained as a nephrologist, was head of the Nuffield Department of Clinical Medicine at the University of Oxford until 2016, when he became Clinical Research Director at the Francis Crick Institute. Through his research on the cellular mechanisms of EPO and its interaction between the kidneys and red cell production, he found that these mechanisms for cellular detection of hypoxia, a state of low oxygen concentration, were also present in several other organs such as the spleen and brain. Virtually all tissues could sense oxygen in their micro-environment, and they could be modified to give them oxygen-sensing capabilities.

Dr. Kaelins findings had shown that the protein made by the VHL gene was somehow involved in controlling the response to low oxygen concentrations. Dr. Ratcliffe and his group made the connection through their discovery that the protein made by the VHL gene physically interacts with HIF complex, marking it for degradation at normal oxygen levels.

In 2001, both groups published similar findings that demonstrated cells under normal oxygen levels will attach a small molecular tag to the HIF complex that allows the VHL protein to recognize and bind HIF, marking it for degradation by enzymes. If the oxygen concentration is low, the HIF complex is protected from destruction. It begins to accumulate in the nucleus where it binds to a specific section of the DNA called hypoxia-regulating genes, which sets into motion the necessary mechanisms to respond to the low oxygen concentration.

The ability to sense oxygen plays a vital role in health and various disease states. Patients who suffer from chronic kidney failure also suffer from severe anemia because their ability to produce EPO is limited. This hormone is necessary for the stem cells in our bone marrow to produce red blood cells. Understanding how cancer cells utilize oxygen-sensing mechanisms has led to a variety of treatments that targets these pathways. The ability to elucidate these mechanisms offers insight into directions scientists and researchers can take to design or create novel treatments.

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The 2019 Nobel Prize in Medicine awarded for research in cellular responses to oxygen - World Socialist Web Site

A novel drug may prevent red blood cells from assuming a mutant, sickled shape.

By Meredith WadmanSep. 17, 2019 , 4:25 PM

A new drug for sickle cell disease, a grave genetic malady that afflicts an estimated 100,000 people in the United States alone and has no truly effective therapy, should be cause for rejoicing. Instead, what could be a rapid march to approval for voxelotor, which acts directly on the mutant protein that causes the disease, has sparked a dispute over the U.S. Food and Drug Administrations (FDAs) efforts to evaluate an urgently needed therapy.

This month, the drugs developer, Global Blood Therapeutics (GBT) in South San Francisco, California, revealed that FDA has launched a priority review of voxelotor and does not plan to have a group of external experts provide advice on the matter before a 26 February 2020 deadline. Critics of the drug expect FDA will give a green light to the therapy, and they say approval would be premature. The drug improves surrogate endpoints that can be measured in lab tests but has not yet been proved to reduce the diseases symptoms. Why are we approving a drug that hasnt shown that it has clinically meaningful benefit? asks Robert Kruse, apathologist at Johns Hopkins Hospital in Baltimore, Maryland, who treats sickle cell patients.

Sickle cell disease originated in Africa, where its estimated to prematurely kill 50% to 90% of the millions of people born with it. A mutation that alters the oxygen-carrying protein hemoglobin inside red blood cells is the culprit. Normal red blood cells are flexible enough to squeeze through small blood vessels. But the mutation causes hemoglobin to aggregate into rock-hard rods that give cells a sickle shape. Sickled cells clump, blocking blood vessels and triggering episodes of intense pain called vaso-occlusive crises. The cells are also brittle and prone to shattering, causing anemia that, in the long term, starves organs of oxygen. That leads to serious problems, such as kidney failure and strokes, and often to early death.

Voxelotor attaches to the mutant hemoglobin and, by increasing its affinity for oxygen, prevents it from aggregating. (Only deoxygenated hemoglobin causes sickling.) In June, The New England Journal of Medicine (NEJM) published a phase III clinical trial of 274 sickle cell patients in which the drug produced significant improvements in blood hemoglobin levels and in two measures of red blood cell destruction over a 24-week period. But it failed to significantly reduce vaso-occlusive crises. GBTs CEO Ted Love says the published trial was too short and had too few patients to show a statistically significant drop in such crises.

To Ashley Valentine, co-founder of Sick Cells, a patient advocacy group based in Naperville, Illinois, The FDA is absolutely doing the right thing by speeding voxelotors review. The drug is a game changer because it attacks the root cause of the disease, she says. (Valentine, whose brother has sickle cell disease, this year joined GBTs community advisory board and was paid $1000 to attend an August meeting.)

FDAs regulations allow approval of a drug based only on surrogate endpoints, if it addresses an unmet medical need and the condition is serious. And the agency has increased such approvals in recent years. But in the past, sickle cell drugs had to reduce the number of painful crises in order to win approval, and voxelotors skeptics say its data are simply not compelling. Theres a famous saying in medicine: Dont treat numbers, treat the patient. This very much feels like we are treating a number and not the patient, Kruse says.

Elliott Vichinsky, a pediatric hematologist at the University of California, San Francisco, Benioff Childrens Hospital in Oakland, and first author on the NEJM paper, counters that rigid requirements that sickle cell [drug trial] outcomes should be based on pain events are very narrow minded. (Vichinsky is a paid adviser to GBT.)

Alexis Thompson, a hematologist at Northwestern Universitys Feinberg School of Medicine in Chicago, Illinois, adds that organ damage is the primary contributor to the shortened life span in sickle cell disease. To the extent that the drugs effects on hemoglobin prevent sickling, she says, its likely to reduce organ injury in the long run. Still, she adds: My response at this point is somewhat measured. I am certainly looking forward to additional clinical trials for this drug.

Other researchers worry about under-the-radar side effects. By making the mutant hemoglobin bind more tightly to oxygen, the drug could keep oxygen from being released in the brain and lead to silent strokes, for which those with sickle cell disease are already at risk, argues hematologist Robert Hebbel at the University of Minnesota Medical School in Minneapolis. The phase III trial did not include the extensive neurological exams required to detect them, he notes.

FDA could still ask outside experts to review voxelotor. And when it grants approvals based on surrogate endpoints, the agency requires companies to conduct additional trials to prove a drug clinically benefits patients. If these fail, approval can be withdrawn.

Such follow-up is crucial, stresses Arthur Caplan, a bioethicist at New York Universitys School of Medicine in New York City. He understands FDAs urgency to approve more therapies for a big, terrible disease. But you are gambling when you go fast. The more permissive you are about skipping regulatory steps, the deeper the obligation to monitor your subjects really, really closely.

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A new sickle cell drug could soon get U.S. approval. But does it work? - Science Magazine

MOUNTAIN VIEW, Calif.--(BUSINESS WIRE)--

The SanBio Group (SanBio Co., Ltd. and SanBio, Inc.)(4592.T), a scientific leader in regenerative medicine for neurological disorders, today announced that the U.S. Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) Designation for SB623 cell therapy for the treatment of chronic neurological motor deficits secondary to traumatic brain injury (TBI). The designation is based on clinical results of SB623 including the Phase 2 Study of Modified Stem Cells in Traumatic Brain Injury (STEMTRA) trial.

Created under the 21st Century Cures Act, the RMAT designation is reserved for a regenerative medicine therapy intended to treat, modify, reverse, or cure a serious condition, and clinical evidence indicates that the therapy has the potential to address unmet medical needs for such disease or condition. Similar to the Breakthrough Therapy designation, the RMAT designation offers sponsors of cell and gene therapies eligibility for expedited development and regulatory review of their product candidate, including earlier and more frequent consultation with the FDA, and the potential for Priority Review and Accelerated Approval.

The RMAT designation for SB623 is an important regulatory milestone for SanBio as we investigate it as a treatment option for patients with chronic neurological motor deficits resulting from a traumatic brain injury, said Bijan Nejadnik, M.D., Chief Medical Officer and Head of Research. TBIs are one of the most common health conditions worldwide that often cause long-term complications or death. We look forward to working with the FDA on a potentially accelerated clinical development program to address this serious unmet medical need.

The RMAT designation augments the Sakigake Designation for innovative medical products from the Ministry of Health, Labour, and Welfare of Japan.

About SB623 SB623 is a proprietary, cell-based investigational product made from modified and cultured adult bone marrow-derived mesenchymal stem cells that undergo temporary genetic modification. Implantation of SB623 cells into injured nerve tissue in the brain is expected to trigger the brains natural regenerative ability to recover lost motor functions.

SanBio expects to initiate a Phase 3 trial for SB623 for the treatment of chronic neurological motor deficits secondary to TBI by the end of the fiscal year ending January 31, 2021. SB623 is also currently in a Phase 2b clinical trial for treatment of chronic motor deficit resulting from ischemic stroke.

About the Study of Modified Stem Cells in Traumatic Brain Injury (STEMTRA) Trial STEMTRA was a 12-month, Phase 2, randomized, double-blind, surgical sham-controlled, global trial evaluating the efficacy and safety of SB623 compared to sham surgery in patients with stable chronic neurological motor deficits secondary to TBI. In this study, SB623 cells were implanted directly around the site of brain injury.

To be eligible for this trial, patients (ages 18-75) must have been at least 12 months post-TBI and had a Glasgow Outcome Scale extended (GOS-E) score of 3-6 (e.g., moderate or severe disability). Patients must also have been able to undergo all planned neurological assessments and had no seizures in the prior three months. The primary endpoint was mean change from baseline in Fugl-Meyer Motor Scale (FMMS) score which measures changes in motor impairment at six months. The STEMTRA trial enrolled 61 patients from 13 surgical and 18 assessment sites in the U.S., Japan and Ukraine.

In this study, SB623 met its primary endpoint, with patients treated with SB623 achieving an average 8.3 point improvement from baseline in the FMMS, versus 2.3 in the control group, at 24 weeks (p=0.040). Of patients treated with SB623, 18 (39.1%) reached a 10 or more point improvement of FMMS compared to one control patient (6.7%; p=0.039). No new safety signals were identified. The most commonly reported adverse event were headaches.

About SanBio Group (SanBio Co., Ltd. and SanBio, Inc.) SanBio Group is a regenerative medicine company with cell-based products focused on neurological disorders in various stages of research, development and clinical trials. The Companys lead asset, SB623, is currently being investigated for the treatment of several conditions including chronic neurological motor deficit resulting from ischemic stroke and traumatic brain injury. SanBio has received a Japanese marketing license for regenerative medicine products from the Tokyo Metropolitan Government, and plans to begin marketing regenerative medicine products in Japan by the end of the fiscal year ending January 31, 2021. The Company is headquartered in Tokyo, Japan and Mountain View, California, and additional information about SanBio Group is available at https://sanbio.com.

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SanBio Granted Regenerative Medicine Advanced Therapy Designation from the U.S. FDA for SB623 for the Treatment of Chronic Neurological Motor Deficits...