NIH, Gates Foundation aim to bring genetic cures to the poor – STAT

The National Institutes of Health and the Bill and Melinda Gates Foundation will together invest at least $200 million over the next four years to develop gene-based cures for sickle cell disease and HIV with an attribute even rarer in the world of genetic medicine than efficacy, the groups announced on Wednesday: The cures, they vowed, will be affordable and available in the resource-poor countries hit hardest by the two diseases, particularly in Africa.

The effort reflects growing concerns that scientific advances in genetic medicine, both traditional gene therapies and genome-editing approaches such as CRISPR, are and will continue to be prohibitively expensive and therefore beyond the reach of the vast majority of patients. Spark Therapeutics Luxturna, a gene therapy for a rare form of blindness, costs $425,000 per eye, for instance, and genetically engineered T cells (CAR-Ts) to treat some blood cancers cost about the same.

With CRISPR-based treatments already being tested in clinical trials for sickle cell disease, the blood disorder beta thalassemia, and another form of blindness, and with additional CRISPR treatments in development, scientists, ethicists, and health policy experts have grown increasingly concerned that the divide between haves and have-nots will grow ever-wider.

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Gene-based treatments are largely inaccessible to most of the world by virtue of the complexity and cost of treatment requirements, which currently limit their administration to hospitals in wealthy countries, the NIH said in a statement. To help right that, its collaboration with the Gates Foundation aims to develop curative therapies that can be delivered safely, effectively and affordably in low-resource settings.

Scientists whose research focuses on gene-based cures welcomed the infusion of funding and the recognition that genetic cures are on track to be unaffordable to the majority of patients. But they noted one irony. The most effective sickle cell drug, hydroxyurea, has hardly even been studied in sub-Saharan Africa, let alone made widely available. Yet a 2019 study found that giving children the drug cut their death rate by two-thirds and halved the pain crises that are common in sickle cell disease, caused by misshapen red blood cells that cannot flow through blood vessels.

The NIH-Gates collaboration is tremendously exciting and has the potential to have a great impact on sickle cell disease in sub-Saharan Africa, said Dr. Vijay Sankaran of the Dana-Farber/Boston Childrens Cancer and Blood Disorders Center, who has done pioneering research on genetic cures for the disease. But my hesitation is that even the inexpensive therapies we have today, such as hydroxyurea, are largely unavailable there. The question is, how do we best approach this disease, with therapies that are working today or with genetic therapies that might work?

The same concerns surround HIV. Very inexpensive less than $100 per year in the U.S. antiretroviral drugs can keep the virus in check, but only 67% of HIV-positive adults and 62% of HIV-positive in children in east and southern Africa are estimated to be on antiretroviral treatment.

The new collaboration aims to move gene-based cures into clinical trials in the U.S. and countries in sub-Saharan Africa within the next seven to 10 years, and to eventually make such treatments available in areas hardest hit by sickle cell disease and HIV/AIDS. The idea is to focus on access, scalability, and affordability to make sure everybody, everywhere has the opportunity to be cured, not just those in high-income countries, NIH Director Francis Collins said in a statement. We aim to go big or go home. But the challenge is enormous, he told reporters on Wednesday: Im not going to lie. This is a bold goal.

An estimated 95% of the 38 million people with HIV live in the developing world, with 67% in sub-Saharan Africa. Up to 90% of children with sickle cell disease in low-income countries die before they are 5 years old. In the U.S., the life expectancy for people with sickle cell disease is in the low 40s.

The NIH and the Gates Foundation will fund research to identify potential gene-based cures for sickle cell and HIV, and also work with groups in Africa to test those cures in clinical trials.

The science of genetic cures for both diseases is within reach, experts say. CRISPR Therapeutics and Vertex (VRTX) are already running a clinical trial for sickle cell disease, using the CRISPR genome editor to do an end-run around the disease-causing mutation in the hemoglobin gene: The therapy releases the brake on red blood cells production of fetal hemoglobin, whose production shuts off in infancy but which does not have the sickling damage of adult hemoglobin.

Developing effective, safe genetic cures for sickle cell and HIV would be only a first step, however. As currently conceived, such therapies require advanced medical facilities to draw blood from patients, alter their cells genomes in a lab, give the patients chemotherapy to kill diseased blood-making cells, and then perform whats essentially a bone marrow transplant, followed by monitoring patients in a hospital for days to prevent infection and provide intensive medical support, said Dr. Dan Bauer, a sickle cell expert at Boston Childrens.

He called the NIH-Gates effort terrific, but cautioned that delivering advanced gene therapies requires tremendous effort, extended hospitalization, and large supplies of blood products. All of those requirements mean that even if a CRISPR-based cure for sickle cell disease or HIV were provided at cost, there will still be barriers to access.

Recognizing that, Collins said, a genetic cure would have to be given directly into patients (in vivo), presumably through an infusion, rather than by treating blood or other cells removed from patients and genetically transformed in a lab (ex vivo). That could avoid the resources needed for and the complications that can occur with ex vivo therapies, said Sankaran, who has discussed the approach with Gates officials.

This story has been updated with additional comments.

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NIH, Gates Foundation aim to bring genetic cures to the poor - STAT

Green Tea Acts as a "Remote Control" To Switch on Cell Therapy – Technology Networks

Let's play a game of word association. I'll go first.

Cell Therapy

What words spring to mind? CRISPR? Medicine? Genetic disorders? Cancer? Gene therapy?

What about green tea? Unlikely, I imagine.

But in a new study published today in Science Advances, researchers from East China Normal University have created an elegant system for activating genetically edited cells using green tea.1Realizing the promise of cell therapiesEngineered cell therapies, deemed the "next frontier" in modern medicine, contain specific cellular material that triggers a desired effect in vitro or in vivo. Such therapies are in development in laboratories across the globe for an array of different conditions, including acute myocardial infarction (heart attack), brain cancer, breast cancer, diabetes and liver diseases. They offer a novel avenue of therapeutics for patients suffering from diseases for which treatment options are limited.For their efficacious and safe use in the clinic, scientists need to be able to regulate the activity of these cells in vivo. Essentially, they require a "remote control". This has proven a major barrier for the delivery of cell therapies to patients. Initial work in this field has adopted antibiotics such as doxycycline or tetracycline as remote-control triggers for gene expression in the cells. However, regular use of antibiotics may result in antibiotic resistance and other adverse side effects.So, what alternatives exist?Haifeng Ye, Professor at East China Normal University, says "Ideal trigger molecules for clinical biomedical applications would be natural, non-toxic, highly soluble, inexpensive, and perhaps even beneficial to health."Previous studies have reported that remote control switches can be activated through the use of food or cosmetic preservatives, vanillic acid, benzoate and phloretin for example. These molecules do not naturally occur in food however, and the safety implications of their long-term use is not well known.A green solution?Nothing beats a good cup of tea. It is the second most popular beverage on the planet (following water) and can be found in the household cupboards of 80% of Americans. Tea is available in a variety of forms, including but not limited to black tea, oolong tea, white tea and green tea. A plethora of research studies have documented the numerous health benefits of green tea consumption, including anticarcinogenic, anti-inflammatory, antimicrobial, and antioxidant effects.The components of green tea most heavily researched with regards to health are the polyphenols, of which the most pertinent are flavonoids, and the most pertinent flavonoids are the catechins.2Post green-tea consumption, the tea catechins and phenolic acids undergo metabolic processing to form the antioxidant protocatechuic acid (PCA). In their latest study, Ye and team have utilized this antioxidant as a "remote control" for activating gene switches in cells. "PCA is a major tea catechin compound produced by humans following green tea consumption that has powerful antioxidant activity. Therefore, in this study, we showed the use of protocatechuic acid (we call it PCA), a metabolite after tea drinking, as a trigger molecule," Ye told Technology Networks.PCA-inducible gene switchesIn the study, the scientists engineered PCA-inducible gene switches in mammalian cells. Initially, they explored the potential for using PCA to monitor cell-based long-term therapies in vivo by integrating the genetic switch into HEK-293 cells and found that the cell line demonstrated reversible and tunable induction kinetics, which the authors regard as "excellent switching performance". This was characterized by negligible basal expression and nonsaturating increases in the transgene output over the course of a 15-day trial.Next, they microencapsulated and implanted the HEK cells into mice. Ye tells us, "The alginate-poly (L-lysine)-alginate-based encapsulation technology was used in our study for cell therapy. This clinically validated implant technology enables the free diffusion of metabolites, nutrients and proteins of lower molecular weights (<72 kDa) across the biocompatible capsule membrane while shielding their cellular content from physical contact with the hosts immune system. The implant technology has been successfully validated in human clinical trials and the performance of the material is continuously improved for clinical applications."The researchers found that, regardless of delivery method (intraperitoneal, oral intake from water, or oral intake from concentrated green tea), PCA could control the secretion of a reporter protein, SEAP, in a dose-dependent manner.Making CRISPR more crisp?CRISPR gene-editing shows promise in revolutionizing personalized medicine. A notable key issue with CRISPR, however, is the "off target" effects that limit its specificity. In this study, the scientists used the PCA-responsive cells to perform more targeted CRISPR gene editing: "By applying newly-designed fusion-protein-based PCA-controlled gene switches to Pol III promoters, we created trigger-inducible expression systems for gRNAs to program PCA-mediated CRISPR/Cas9-activity," says Ye.Exploring diabetes treatment with PCA-induced cell therapyYe and colleagues next tested the potential of the PCA remote control system for treating experimental diabetes using a mouse model. Using the switch, they engineered two different cell lines: one that enabled PCA-inducible expression of the reporter protein SEAP and insulin, and the other producing a short variant of human glucagon-like peptide 1 and SEAP. Implantation of these cells into mouse models of type 1 diabetes and type 2 diabetes mellitus resulted in restored homeostatic fasting blood glucose concentrations and glucose tolerance upon PCA injection.Recognizing that the translation of research findings from mouse models to humans in the clinic can be problematic, the scientists then decided to explore the PCA remote control switch efficacy in non-human primate models of diabetes. In parallel to the treatment efficacy observed in the type 2 diabetic mice, daily oral administration of PCA rapidly increased the expression of glucagon-like peptide 1 and restored glucose homeostasis in diabetic monkeys.In terms of safety, blood biochemical analyses related to inflammatory responses found that white blood cell count, lymphocytes, monocytes, eosinophils, and basophils, did not increase at any point during the treatment when compared with pre-treatment.The study findings certainly excite the authors, "Although there have not yet been preclinical studies for the application of engineered cellbased therapies in humans, this first-in-monkey study demonstrates the feasibility of safely and successfully scaling up a treatment strategy by controlling microencapsulated engineered cells to release therapeutic outputs from animals such as mice to larger NHPs. Therefore, this study substantiates the medical utility of concepts developed in synthetic biology," they note in the discussion of the paper.How much tea is too much tea?Hypothetically, if this therapy was to reach the clinic, I ponder over the possibility of an individual consuming "too much" green tea, and how this might impact the therapy. Ye is quick to inform me that this would not be an issue, "Only custom prepared concentrated green tea can activated the implanted designer cells. The normal green tea drinks cannot activate the implanted cells because of low concentration," he says.The future looks greenThe study is comprehensive, assessing the PCA "switch" in a variety of cell lines and mammalian models with a variety of control measures in place.Thus, in which direction will this research go next? I ask Ye, who tells me, " We will next focus on solving the following limitations:(1) The PCAON-switch was stably integrated into [the] genome by a "Sleeping Beauty" transposon system. Due to a random integration, unwanted insertional mutagenesis might occur. We will next consider using gene editing tools, such as CRISPR, to enable facile and permanent integration of the switch into the targeted genomic sequences in human cells without insertional mutagenesis;(2) The chassis of the HEK-293 cells are easily handled, transfected, and compatible to the PCAON-switch. For translational applications, they must also be safe (no side effects) in humans. Hence, we will test the therapeutic efficiency of the PCAON-switch in autologous parental cells from patients own mesenchymal stem cells, which may provide immunocompatible and noncarcinogenic autologous or allogeneic cell sources;(3) The lifespan of the designer cells inside the alginate microcapsules is an imperative issue. To realize long-term cell therapy, we will further improve the encapsulation technology."Haifeng Ye, Professor at East China Normal University, was speaking with Molly Campbell, Science Writer, Technology Networks.References:1. A green teatriggered genetic control system for treating diabetes in mice and monkeys," by J. Yin; L. Yang; K. Dong; J. Jiang; S. Xue; Y. Xu; X. Wang; H. Ye at East China Normal University in Shanghai, China; L. Mou; Y. Lu at First Affiliated Hospital of Shenzhen University in Shenzhen, China.2. Reygaert. 2018. Green Tea Catechins: Their Use in Treating and Preventing Infectious Diseases. Biomed Research International. doi: 10.1155/2018/9105261.

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Green Tea Acts as a "Remote Control" To Switch on Cell Therapy - Technology Networks

Clues to improve cancer immunotherapy revealed – Washington University School of Medicine in St. Louis

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Helper T cells appear vital to more robust anti-tumor response

T cells (blue) can be seen infiltrating a mouse tumor, along with other immune cells (in green, purple and yellow). Researchers at Washington University School of Medicine in St. Louis have demonstrated in a new study that both killer and helper T cells are needed for tumors to be rejected during cancer immunotherapy.

Cancer immunotherapy drugs trigger the bodys immune system to attack tumors and have revolutionized the treatment of certain cancers, such as lymphoma, lung cancer and melanoma. Yet, while some patients respond well to the drugs, others dont respond at all. Cancer immunologists want to change that.

A new study by researchers at Washington University School of Medicine in St. Louis indicates a way for cancer immunotherapy to spur a more robust immune response. Such knowledge could lead to the development of better cancer vaccines and more effective immunotherapy drugs called checkpoint inhibitors.

The study is published Oct. 23 in the journal Nature.

Immunotherapy presents tremendous promise for cancer treatment, but we havent yet found a way to make it widely effective, said senior author Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor. It still doesnt work for many patients, particularly for common cancers, such as breast or prostate. We want to understand why they are ineffective in these cases so we can make better therapies. Our research suggests that immunotherapy is likely to be more effective when a vaccine is used alongside checkpoint inhibitors.

Much immunotherapy for cancer is designed to prompt immune cells called killer T cells to attack the cancer cells. But the new research suggests that also recruiting other T cells called helper T cells could boost the effectiveness of immune therapy. Such helper T cells are involved in recognizing cancer as a threat and recruiting killer T cells to mount an attack. Without the helper cells, the immune system typically doesnt fully respond to fight cancer.

This study reveals for the first time that helper T cells are essential in cancer immunotherapy, said Schreiber, who directs Washington Universitys Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs. Activating killer T cells alone is not enough. To work better for all patients, we think effective cancer vaccines and immunotherapy drugs must activate both the killer and helper T cells.

Current cancer vaccines and immune checkpoint therapies are designed with a solid understanding of a group of genes called MHC class I genes that activate killer T cells. The new study delves deep into another group of genes called MHC class II that activate the helper T cells. The research reveals ways to harness knowledge of both of these important components of the immune system to more effectively single out the tumors as dangerous, so that the helper and killer T cells can work together to eliminate the cancer and spare healthy tissues.

Schreibers co-authors, including Maxim N. Artyomov, PhD, an associate professor of pathology & immunology, developed a computer program that can predict which mutant proteins or antigens on a patients tumor will specifically activate helper T cells. This sort of predictive software is well-established for activating killer T cells. But until now, this was largely impossible for helper T cells.

For killer T cells, were relatively good at looking at a patients tumor, seeing what mutations are present and figuring out which mutations are most likely to trigger killer T cells to respond, said first author Elise Alspach, PhD, a postdoctoral research associate in Schreibers lab. But the ability to do this for helper T cells has lagged far behind.

Added Schreiber, Its a bit like finding a needle in a haystack. With all the proteins in tumor cells, how do you find the ones that serve as the best antigens to activate the immune system? We believe the technique that weve developed is an important step forward for harnessing helper T cells in cancer immunotherapy.

Studying mice with models of human cancer, Schreiber, Alspach and their colleagues showed that immune checkpoint therapy is more effective when helper T cells are activated along with killer T cells. They further showed that vaccines also are more effective when targets activating both helper and killer T cells are present.

Just because a killer T cell is present doesnt mean its actively killing tumor cells, Alspach said. We found that not only do you need helper T cells to recruit the killer T cells, the helper cells need to be there to coax the killer T cells to mature into an active state in which they are capable of killing cells.

And finally, the most effective anti-tumor responses occurred when immune checkpoint therapy was combined with a vaccine that incorporates targets for helper and killer T cells that are specific to antigens in the patients tumor.

The idea of giving checkpoint inhibitors along with a tumor-specific vaccine especially a vaccine that activates both killer and helper T cells is just beginning, Schreiber said. But based on our study, the combination is likely to be more effective than any of the components alone. Today, when we treat a particular tumor type with checkpoint inhibitors, maybe 20 percent of the patients respond well. Were hoping that with a vaccine plus checkpoint inhibitors, the number of patients who respond well will go up to 60 or 70 percent. We havent tried that yet in patients, but thats the hope.

This work was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH), grant number RO1CA190700; the Parker Institute for Cancer Immunotherapy; the Cancer Research Institute; Janssen Pharmaceutical Co. of Johnson and Johnson; the Prostate Cancer Foundation; and a Stand Up to Cancer-Lustgarten Foundation Pancreatic Cancer Foundation Convergence Dream Team Translational Research Grant. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. This work was further supported by a postdoctoral training grant from the NCI, grant number T32 CA00954729; the Irvington Postdoctoral Fellowship from the Cancer Research Institute; a St. Baldricks Scholarship from Hope with Hazel; and a Pew-Stewart Scholarship for Cancer Research supported by the Pew Charitable Trusts. Additional support was provided by the NCI through a Paul Calabresi Career Development Award in Clinical Oncology, grant number K12CA167540; a Parker Bridge Scholar Award from the Parker Institute for Cancer Immunotherapy; the NIH, grant number R01CA238039; an NIH Cancer Center Support Grant, number P30CA14051; and the Howard Hughes Medical Institute. Other support was provided by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH, grant numbers AI114551 and DK058177; the Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs; and Siteman Cancer Center, supported by the NCI of the NIH Cancer Center Support Grant, number P30CA91842.

Alspach E, et al. MHC-II neoantigens shape tumor immunity and response to immunotherapy. Nature. Oct. 23, 2019.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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United Therapeutics receives permit for cell therapy facility build-out at Mayo – Jacksonville Daily Record

United Therapeutics received a building permit Tuesday for a $9.5 million build-out of its cell therapy facility on the second floor of Mayo Clinics Discovery and Innovation Building.

The 21,843-square-foot space will house an automated stem cell manufacturing site, which is one of the first of its kind in the country. The Whiting-Turner Contracting Co. is the project contractor.

The technology, approved by the FDA in 2018, allows the Mayo Clinic Center for Regenerative Medicine to produce cells from the bone marrow of a stem cell donor in large enough quantities to be used as treatments in clinical trials. It allows for the treatment of multiple patients at the same time.

Construction began in 2017 on the $32.4 million building at 14221 Kendall Hench Drive. It held a grand opening in August.

The first floor houses three ex-vivo lung perfusion surgical suites used for lung restoration, another form of regenerative medicine. It turns donor lungs, which previously would have previously been unusable, into viable transplant organs. United Therapeutics also collaborates with Mayo Clinic on lung restoration.

The third floor houses the Life Sciences Incubator for biotech entrepreneurs, which offers coworking space, wet labs, business resources, networking and entrepreneurial training.

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United Therapeutics receives permit for cell therapy facility build-out at Mayo - Jacksonville Daily Record

More Breakthroughs in Nanotechnology Could Lead to Improvements in Drug Delivery and Medicine – BioSpace

Researchers have developed a precise and non-toxic nanoscale technology that can deliver oncology drugs directly to cancer cells. The minuscule tubes are called peptoids.

The research was led by Yuehe Lin, professor at Washington State Universitys School of Mechanical and Materials Engineering and Chun-Long Chen, senior research scientist at the Department of Energys Pacific Northwest National Laboratory (PNNL) and joint faculty member at University of Washington. The study was published in the journal Small.

The peptoids are about a thousand times thinner than a human hair. The researchers took the nanotubes, which were inspired by biological models, and rolled them into nanosheet membranes. They were then able to use a variety of drugs, fluorescent dyes and cancer-targeting molecules and place them into the nanotubes, which allowed them to track the drug delivery.

The two drugs they used were a chemotherapy agent and a less-invasive photodynamic therapy. Photodynamic therapeutic compounds release reactive oxygen species (ROS) that kill cancer cells when exposed to light. The combination therapy allowed the researchers to use lower doses of the chemotherapeutic, which decreased the toxicity.

By precisely engineering these nanotubes with fluorescent dyes and cancer targeting molecules, scientists can clearly locate tumor cells and track how the drug regimen is performing, said Lin. We can also track how nanotubes enter and deliver the drugs inside the cancer cell.

They evaluated the peptoids on lung cancer cells. The chemotherapy drug was doxorubicin. The system delivered the drug directly to the cancer cells, which resulted in what it describes as highly efficient cancer killing, all while using much lower doses of doxorubicin.

This is a promising approach for precision targeting with little damage to healthy surrounding cells, Lin said.

What is new about the research is the use of the peptoids. Other research has been conducted using carbon nanotubes and other nanomaterials, but there are toxicity issues. They also werent as effective at precisely recognizing molecules.

By using these peptoids, we were able to develop highly programmable nanotubes and a biocompatible delivery mechanism, Chen said. We also harnessed the high stability of peptoid and its well-controlled packing to develop nanotubes that are highly stable.

Research into nanotechnology is making progress, although its not clear just how much of it, if any, is making it into clinical applications. In August, researchers at Rutgers University-New Brunswick published research about a nanotechnology platform that helps identify what happens to specific stem cells.

Stem cells are key building blocks that can differentiate into all the different types of cells in the body, including brain cells and heart cells and skin cells. Increasingly, researchers are utilizing adult human-induced pluripotent stem cells (iPSCs) to develop drugs and work on therapies.

The researchers monitored the creation of neurons from human stem cells by identifying next-generation biomarkers called exosomes. Exosomes are particles released by cells and they play a critical function in cell-to-cell communication.

One of the major hurdles in the current cell-based therapies is the destructive nature of the standard cell characterization step, stated senior author KiBum Lee, professor in the Department of Chemistry and Chemical Biology. With our technology, we can sensitively and accurately characterize the cells without compromising their viabilities.

The technology platform utilizes minuscule nanotubes for sensing. Specifically, the authors reported using a multifunctional magneto-plasmonic nanorid (NR)-based detection platform.

Researchers at Texas Heart Institute (THI) recently used bio-compatible nanotubes invented at Rice University to restore electrical function to damaged hearts.

Instead of shocking and defibrillating, we are actually correcting diseased conduction of the largest major pumping chamber of the heart by creating a bridge to bypass and conduct over a scarred area of a damaged heart, stated Mehdi Razavi, a cardiologist and director of Electrophysiology Clinical Research and Innovations at THI. Razavi co-led the study with Matteo Pasquali, a chemical and biomolecular engineer at Rice University.

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More Breakthroughs in Nanotechnology Could Lead to Improvements in Drug Delivery and Medicine - BioSpace