Stem Cell Clinic

Orchard Therapeutics Announces FDA Granted Orphan Drug Designation for OTL-102 for the Treatment of X-linked Chronic Granulomatous Disease (X-CGD) -…

Early Clinical Data Support ex vivo Hematopoietic Stem Cell Gene Therapy as a Potentially Promising Treatment Option for X-CGD

BOSTON and LONDON, Jan. 29, 2020 (GLOBE NEWSWIRE) -- Orchard Therapeutics (ORTX), a global gene therapy leader, today announced that it has received orphan drug designation from the U.S. Food and Drug Administration (FDA) for OTL-102, the companys ex vivo autologous hematopoietic stem cell (HSC) gene therapy being investigated for the treatment of X-linked chronic granulomatous disease (X-CGD). The FDA may grant orphan designation to drugs and biologics intended to treat a rare disease or condition affecting fewer than 200,000 persons in the U.S.

We are pleased to have received this orphan drug designation from the FDA, which recognizes the potential of OTL-102 to address a rare population of patients with X-CGD, a life-threatening disease with a critical unmet need, said Anne Dupraz-Poiseau, Ph.D., chief regulatory officer at Orchard. We are encouraged by the clinical data published to date and are eager to advance OTL-102 development as quickly as possible for patients with X-CGD.

Orphan designation qualifies a company for certain benefits, including financial incentives to support clinical development and the potential for seven years of market exclusivity in the U.S. upon regulatory approval.

Early academic clinical trial data for OTL-102 that was recently published in Nature Medicine demonstrates that ex vivo autologous HSC gene therapy may be a promising approach for the treatment of X-CGD. The letter, which wasled by researchers at the University of California, Los Angeles (UCLA)including Donald B. Kohn, M.D., one of the study's lead investigators and professor of microbiology, immunology and molecular genetics at UCLA and Great Ormond Street Hospital (UK), provides an analysis of safety and efficacy outcomes in nine severely affected patients with X-CGD. At 12 months post-treatment, six of seven surviving patients, all of whom were adults or late adolescents, exceeded the minimum threshold hypothesized in published literature to demonstrate potential clinical benefit, defined as 10% functioning, oxidase-positive neutrophils in circulation and have discontinued preventive antibiotics.1

As previously reported, two pediatric patients died within three months of treatment from complications deemed by the investigators and independent data and safety monitoring board to be related to pre-existing comorbidities due to advanced disease progression and unrelated to OTL-102. Investigators are planning to enroll additional pediatric patients in 2020 to assess outcomes in this patient population. In addition, there is work underway to improve the efficiency of the drug product manufacturing process prior to initiating a registrational study.

Patients with X-CGD experience significantly reduced quality and length of life, and currently must take daily medications that do not eliminate the risk of fatal infections, said Adrian Thrasher, Ph.D., M.D., one of the studys lead investigators and professor of pediatric immunology and Wellcome Trust Principal Research Fellow at UCL Great Ormond Street Institute of Child Health in London. These data demonstrate that OTL-102 has the potential to become a transformative new treatment option for patients with X-CGD with the evaluation of longer follow up and more patients.

About X-CGDX-linked chronic granulomatous disease (X-CGD) is a rare, life-threatening, inherited disease of the immune system caused by mutations in the cytochrome B-245 beta chain (CYBB) gene encoding the gp91phox subunit of phagocytic NADPH oxidase. Because of this genetic defect, phagocytes, or white blood cells, of X-CGD patients are unable to kill bacteria and fungi, leading to chronic, severe infections. The main clinical manifestations of X-CGD are pyoderma, a type of skin infection; pneumonia; colitis; lymphadenitis, an infection of the lymph nodes; brain, lung and liver abscesses; and osteomyelitis, an infection of the bone. Patients with X-CGD typically start to develop infections in the first decade of life, and an estimated 40 percent of patients die by the age of 35.2 The incidence of X-CGD is currently estimated at between 1 in 100,000 and 1 in 400,000 male births.

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About OTL-102OTL-102 is an ex vivo autologous hematopoietic stem cell gene therapy being studied for the treatment of X-CGD. The studies are supported by multiple institutions including the California Institute of Regenerative Medicine, the Gene Therapy Resource Program from the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases Intramural Program, the Wellcome Trust and the National Institute for Health Research Biomedical Research Centres at Great Ormond Street Hospital for Children NHS Foundation Trust, University College London Hospitals NHS Foundation Trust and University College London. Preclinical and clinical development of OTL-102 had originally been initiated by Genethon (Evry, France) and funded by an EU framework 7 funded consortium, NET4CGD, before being licensed to Orchard.

About OrchardOrchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically-modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. The company has one of the deepest gene therapy product candidate pipelines in the industry and is advancing seven clinical-stage programs across multiple therapeutic areas, including inherited neurometabolic disorders, primary immune deficiencies and blood disorders, where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit http://www.orchard-tx.com, and follow us on Twitter and LinkedIn.

Forward-Looking StatementsThis press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, plans, intends, projects, and future or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release, Orchards expectations regarding the timing of regulatory submissions for approval of its product candidates, including the product candidate or candidates referred to in this release, the timing of interactions with regulators and regulatory submissions related to ongoing and new clinical trials for its product candidates, the timing of announcement of clinical data for its product candidates and the likelihood that such data will be positive and support further clinical development and regulatory approval of these product candidates, and the likelihood of approval of such product candidates by the applicable regulatory authorities. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, without limitation: the risk that any one or more of Orchards product candidates, including the product candidate or candidates referred to in this release, will not be successfully developed or commercialized, the risk of cessation or delay of any of Orchards ongoing or planned clinical trials, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates,the delay of any of Orchards regulatory submissions, the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates, the receipt of restricted marketing approvals, and the risk of delays in Orchards ability to commercialize its product candidates, if approved. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards annual report on Form 20-F for the year ended December 31, 2018, as filed with the U.S. Securities and Exchange Commission (SEC) on March 22, 2019, as well as subsequent filings and reports filed with the SEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

References1Kang et al. Blood. 2010;115(4):783-912van den Berget al. PLoS One. 2009;4(4):e5234

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaMolly CameronManager, Corporate Communications+1 978-339-3378media@orchard-tx.com

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Orchard Therapeutics Announces FDA Granted Orphan Drug Designation for OTL-102 for the Treatment of X-linked Chronic Granulomatous Disease (X-CGD) -...

Snake venom can now be made in a lab and that could save many lives – CNN

It involves milking snake venom by hand and injecting it into horses or other animals in small doses to evoke an immune response. The animal's blood is drawn and purified to obtain antibodies that act against the venom.

Producing antivenom in this way can get messy, not to mention dangerous. The process is error prone, laborious and the finished serum can result in serious side effects.

Experts have long called for better ways to treat snake bites, which kill some 200 people a day.

Now -- finally -- scientists are applying stem cell research and genome mapping to this long-ignored field of research. They hope it will bring antivenom production into the 21st Century and ultimately save thousands, if not hundreds of thousands, of lives each year.

Researchers in the Netherlands have created venom-producing glands from the Cape Coral Snake and eight other snake species in the lab, using stem cells. The toxins produced by the miniature 3-D replicas of snake glands are all but identical to the snake's venom, the team announced Thursday.

"They've really moved the game on," said Nick Cammack, head of the snakebite team at UK medical research charity Wellcome. "These are massive developments because it's bringing 2020 science into a field that's been neglected."

Hans Clevers, the principal investigator at the Hubrecht Institute for Developmental Biology and Stem Cell Research in Utrecht, never expected to be using his lab to make snake venom.

So why did he decide to culture a snake venom gland?

Clevers said it was essentially a whim of three PhD students working in his lab who'd grown bored of reproducing mouse and human kidneys, livers and guts. "I think they sat down and asked themselves what is the most iconic animal we can culture? Not human or mouse. They said it's got to be the snake. The snake venom gland."

"They assumed that snakes would have stem cells the same way mice and humans have stems cells but nobody had ever investigated this," said Clevers.

After sourcing some fertilized snake eggs from a dealer, the researchers found they were able to take a tiny chunk of snake tissue, containing stem cells, and nurture it in a dish with the same growth factor they used for human organoids -- albeit at a lower temperature -- to create the venom glands. And they found that these snake organoids -- tiny balls just one millimeter wide -- produced the same toxins as the snake venom.

The team compared their lab-made venom with the real thing at the genetic level and in terms of function, finding that muscle cells stopped firing when exposed to their synthetic venom.

The current antivenoms available to us, produced in horses not humans, trigger relatively high rates of adverse reactions, which can be mild, like rash and itch, or more serious, like anaphylaxis. It's also expensive stuff. Wellcome estimate that one vial of antivenom costs $160, and a full course usually requires multiple vials.

Even if the people who need it can afford it -- most snakebite victims live in rural Asia and Africa -- the world has less than half of the antivenom stock it needs, according to Wellcome. Plus antivenoms have been developed for only around 60% of the world's venomous snakes.

In this context, the new research could have far-reaching consequences, allowing scientists to create a biobank of snake gland organoids from the 600 or so venomous snake species that could be used to produce limitless amounts of snake venom in a lab, said Clevers.

"The next step is to take all that knowledge and start investigating new antivenoms that take a more molecular approach," said Clevers.

To create an antivenom, genetic information and organoid technology could be used to make the specific venom components that cause the most harm -- and from them produce monoclonal antibodies, which mimic the body's immune system, to fight the venom, a method already used in immunotherapy treatments for cancer and other diseases.

"It's a great new way to work with venom in terms of developing new treatments and developing antivenom. Snakes are very difficult to look after," Cammack said, who was not involved with the research.

Clevers said his lab now plans to make venom gland organoids from the world's 50 most venomous animals and they will share this biobank with researchers worldwide. At the moment, Clevers said they are able to produce the organoids at a rate of one a week.

But producing antivenom is not an area that pharmaceutical companies have traditionally been keen to invest in, Clevers said

Campaigners often describe snakebites as a hidden health crisis, with snakebites killing more people than prostrate cancer and cholera worldwide, Cammack said.

"There's no money in the countries that suffer. Don't underestimate how many people die. Sharks kill about 20 per year. Snakes kill 100,000 or 150,000," said Clevers.

"I'm a cancer researcher essentially and I am appalled by the difference in investment in cancer research and this research."

One challenge to making synthetic antivenom is the sheer complexity of how a snake disables its prey. Its venom contains several different components that have different effects.

Researchers in India have sequenced the genome of the Indian Cobra, in an attempt to decode the venom.

"It's the first time a very medically important snake has been mapped in such detail," said Somasekar Seshagiri, president of SciGenom Research Foundation, a nonprofit research center in India.

"It creates the blueprint of the snake and helps us get the information from the venom glands." Next, his team will map the genomes of the saw-scaled viper, the common krait and the Russell's viper -- the rest of India's "big four." This could help make antivenom from the glands as it will be easier to identify the right proteins.

In tandem, both breakthroughs will also make it easier to discover whether some of the potent molecules contained in snake venom are themselves worth prospecting as drugs -- allowing snakes to make their mark on human health in a different way to how nature intended -- by saving lives.

"As well as being scary, venom is amazingly useful," Seshagari said.

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Snake venom can now be made in a lab and that could save many lives - CNN

Rutgers partners with Horizon Discovery Group | – University Business

A novel base editing technology invented at Rutgers, The State University of New Jersey with the potential to be used for the creation of new cell and gene therapies will be made available to researchers worldwide through an exclusive partnership with the Horizon Discovery Group.

The technology invented by Shengkan Victor Jin, associate professor of pharmacology, and co-inventor Juan C. Collantes, post-doctoral research fellow, at Rutgers Robert Wood Johnson Medical School can be potentially used for developing cell therapies for sickle cell anemia and beta thalassemia, HIV resistant cells for AIDS, off-the-shelf CAR-T cells for cancer, and MHC-compatible allogenic stem cells for transplantation. It could also be used as gene therapies for inherited genetic diseases such as antitrypsin deficiency and Duchenne muscular dystrophy.

The gene editing technology developed by our researchers has the potential to revolutionize how scientists think about their search for better options and outcomes in the treatment of disease worldwide, said S. David Kimball, PhD, Senior Vice President for Research and Economic Development at Rutgers University. Just as important is our ability, through this significant partnership with Horizon Discovery Group, to share our discoveries and inventions with the scientific community around the world who are equally committed to improving human health.

In January 2019, Rutgers University formed an exclusive partnership with Horizon to further the development of the proprietary base editing technology invented by Jin and Collantes. Since the initial partnership, Horizon, a global leader in the application of gene editing and gene modulation technologies, has been funding research in base editing at Jins laboratory. The company has now exercised its option to exclusively license the technology for commercialization of all therapeutic applications. This partnership places Rutgers among the front runners in the field of gene editing.

The technology could have a significant impact in enabling cell therapies to be progressed through clinical trials and towards commercialization. Horizon is pleased to offer an effective and precise base editing technology and, alongside Rutgers, aims to make base editing available to all appropriate cell and gene therapy companies as well as research departments. Partnering with leading organizations will help us to drive innovation and deliver the best therapy for the patient, stated Dr. Jonathan Frampton, Corporate Development Partner, Horizon Discovery.

Horizon has a number of internal programs designed to accelerate the clinical uptake of this technology and is now seeking partners to assess and shape the development of its Pin-point base editing platform. The company will offer partners access to a novel system that could be used to advance more effective multi-gene knockout cell therapy programs, with an improved safety profile, through clinical development. Partners will also gain access to the companys expertise in genome engineering of different cell types, access to early technical data, and influence over the direction of future development.

We intend to take full advantage of the unique modular and versatile features of the Pin-point platform and develop efficient gene inactivation agents for potential treatment of many devastating diseases where the leading causal contributing factors are well-defined. At the top of this disease list are Alzheimers disease, amyotrophic lateral sclerosis, and familial hypercholesterinemia, said Jin.

Base editing is a novel technology for engineering DNA in cells, with the potential to correct certain errors or mutations in the DNA or inactivate disease-causing genes. Compared with currently available gene editing methodologies such as conventional CRISPR/Cas9, which creates cuts in the gene that can lead to adverse or negative effects, this new technology allows for accurate gene editing while reducing unintended genomic changes that could lead to deleterious effects in patients.

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About Rutgers, The State University of New Jersey

Rutgers, The State University of New Jersey, is a leading national research university and the state of New Jerseys preeminent, comprehensive public institution of higher education. Established in 1766, the university is the eighth oldest higher education institution in the United States. More than 70,000 students and 23,400 full- and part-time faculty and staff learn, work, and serve the public at Rutgers locations across New Jersey and around the world.www.rutgers.edu

As the premier public research university in the state, Rutgers is dedicated to teaching that meets the highest standards of excellence, to conducting cutting-edge research that breaks new ground and aids the states economy, businesses, and industries, and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.research.rutgers.edu

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Rutgers partners with Horizon Discovery Group | - University Business

Equillium to Present Translational Preclinical Data Demonstrating Increased Survival and Decreased Disease Severity in Models of Graft-Versus-Host…

LA JOLLA, Calif., Jan. 29, 2020 (GLOBE NEWSWIRE) -- Equillium, Inc. (Nasdaq: EQ), a clinical-stage biotechnology company leveraging deep understanding of immunobiology to develop products to treat severe autoimmune and inflammatory disorders, today announced that translational data supporting the potential of itolizumab in the treatment of graft-versus-host disease (GVHD) will be presented at the Transplantation & Cellular Therapy (TCT) Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT)and the Center for International Blood & Marrow Transplant Research (CIBMTR) being held February 19-23, 2020 at the World Center Marriott in Orlando, Florida. The research, conducted in mouse models of human disease, demonstrates that blockade of the CD6-ALCAM pathway with anti-CD6 antibodies reduces incidence and severity of both GVHD and gastro-intestinal (GI) inflammation.

Although GVHD is a leading cause of non-relapse mortality in patients following an allogeneic hematopoietic stem cell transplant, there are currently no approved therapies available for first-line treatment, said Robert Soiffer, M.D., chief of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute. This data further validates CD6 as an attractive target to selectively modulate T effector cell activity and as a potential therapeutic approach.

Stephen Connelly, Ph.D., chief scientific officer of Equillium added, We are encouraged by our research demonstrating that the blockade of the CD6-ALCAM pathway reduces the severity of GVHD and improves mortality rates associated with GVHD and GI inflammation in multiple humanized in vivo models, supporting its use as a potential therapy for severe inflammatory disorders driven by T effector cells. We continue to investigate the safety and clinical activity of itolizumab in patients with acute GVHD in the EQUATE trial, an ongoing Phase 1b/2 clinical trial.

Below is the abstract title that has been selected for a poster presentation. Full text of the abstracts can be found on theconference website. Once the TCT poster presentations are made public, they will be available in theInvestors sectionof Equilliums website.

Poster PresentationTitle:Targeting the CD6-ALCAM Pathway to Prevent and Treat Graft vs. Host DiseaseFirst Author:Cherie Ng, Ph.D., MPHDate and Time:February 19, 2020 from 6:30 - 8:00 p.m. ETSession: Poster Session I: Graft-Versus-Host and Graft-Versus-Tumor - Basic/Pre-ClinicalPoster Number: 250

About EquilliumEquillium is a clinical-stage biotechnology company leveraging deep understanding of immunobiology to develop products to treat severe autoimmune and inflammatory disorders with high unmet medical need.

Equilliums initial product candidate, itolizumab (EQ001), is a clinical-stage, first-in-class monoclonal antibody that selectively targets the novel immune checkpoint receptor CD6. CD6 plays a central role in modulating the activity and trafficking of T cells that drive a number of immuno-inflammatory diseases. Itolizumab is a clinically-validated therapeutic that has demonstrated a favorable safety and tolerability profile. Equillium acquired rights to itolizumab through an exclusive partnership with Biocon Limited. Equillium believes that itolizumab has the potential to be a best-in-class disease modifying therapeutic and is advancing the clinical development of itolizumab in the following severe immuno-inflammatory disorders: uncontrolled asthma, acute graft-versus-host disease, and lupus nephritis. For more information, visitwww.equilliumbio.com.

Forward-Looking StatementsStatements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding Equilliums plans for developing itolizumab for the treatment of GVHD and the potential benefits of itolizumab for GVHD. Risks that contribute to the uncertain nature of the forward-looking statements include uncertainties related to the impact of certain translational research, completion of clinical trials and whether the results from clinical trials will validate and support the safety and efficacy of itolizumab for GVHD. These and other risks and uncertainties are described more fully under the caption "Risk Factors" and elsewhere in Equillium's filings and reports with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Equillium undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Investor Contact+1-858-412-5302ir@equilliumbio.com

Media ContactCammy DuongCanale Communications+1-619-849-5389cammy@canalecomm.com

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Equillium to Present Translational Preclinical Data Demonstrating Increased Survival and Decreased Disease Severity in Models of Graft-Versus-Host...

Gladstone Scientists Funded by NIH to Dive Deep Into ApoE4’s Role in Alzheimer’s Disease – Yahoo Finance

With $4.8 million from the NIH, Gladstone scientists will investigate how the protein apoE4 causes neurodegeneration in Alzheimer's disease.

SAN FRANCISCO, Jan. 29, 2020 /PRNewswire/ -- The story of Alzheimer's disease is familiar and heartbreaking. As neurons degenerate and die, patients slowly lose their memories, their thinking skills, and ultimately, their ability to perform basicday-to-day tasks.

For years, clinical trials investigating potential treatments for Alzheimer's disease have come up short. That's why researchers at Gladstone Institutes are delving deeper into the question of what drives this complex disease.

Now, a team led by Senior Investigator and President EmeritusRobert Mahley, MD, PhD, has received $4.8 million from the National Institutes of Health (NIH) to study a promising culprit: apoE4, a protein associated with increased risk of Alzheimer's disease.

ApoE4 is one of the forms of apolipoprotein E, a protein that aids repair processes in neurons injured by aging, stroke, or other causes. The most common form is called apoE3, but apoE4 is not rare: it is found in one-quarter of the human population and in about two-thirds of all Alzheimer's patients, which makes it the most important genetic risk factor for the disorder.

"ApoE4 dramatically rewires cellular pathways in neurons and impairs their function," Mahley said. "Our goal is to understand how this rewiring occurs and identify potential new treatment strategies to negate the detrimental effects."

ApoE3 and apoE4 differ at only a single point in the sequence of their amino acid building blocks. But that single change gives apoE4 a very different shape from apoE3, making it more susceptible to being broken down into smaller fragments within a neuron.

"Our work suggests that these apoE4 fragments are toxic to neurons and cause sweeping changes to the collection of proteins expressed within a neuron," Mahley said. "We suspect that their toxicity may underlie much of the neurodegeneration seen in Alzheimer's disease."

A Powerful Partnership

With the new NIH funding, Mahley hopes to illuminate the specifics of apoE4's toxicity in unprecedented molecular detail. Key to this work is his new partnership with Senior InvestigatorNevan Krogan, PhD, and Gladstone Mass Spectrometry Facility Director Danielle Swaney, PhD, who together have extensive expertise in studying how proteins interact with each other.

To get to the bottom of apoE4's impact, they will use a technique called affinity purification mass spectrometry (AP-MS)to first determine which proteins, out of the thousands found in a single cell, interact directly with apoE4 fragments.

"AP-MS is an important first step because it will allow us to define physical interactions between proteins that may underlie the functional deficits observed in neurons that express apoE4," Swaney said. The AP-MS work will be performed in mouse-derived neuronal cells that are similar to human neurons.

In addition to AP-MS, the collaborators will use other advanced protein analysis techniques perfected in Krogan's lab to better understand the cellular processes that are dysregulated in apoE4-expressing neurons. This additional protein work will be performed in neurons derived from human induced pluripotent stem (hiPS) cells. These stem cells are produced from human skin cells, using the procedure developed byShinya Yamanaka, MD, PhD, a Gladstone senior investigator and 2012 Nobel prize winner.

"We are quite excited to be involved in this project," Krogan said. "My lab has successfully applied AP-MS and other cutting-edge proteomic and genetic techniques to many different diseases, and we now hope to enable a much deeper understanding of apoE4."

When combined, results from the APMS work and the additional protein analyses will reveal a list of key proteins involved in processes that are specifically altered in apoE4 neurons compared to apoE3 neurons.

From that list, Mahley and Swaney will select top candidates for further investigation in neurons grown from hiPS cells. Senior InvestigatorYadong Huang, MD, PhD, who has also studied apoE4 extensively, will provide guidance on the use of the hiPS cells.

Using a gene-editing tool called CRISPR, the researchers will see if they can reverse the detrimental effects of apoE4 by activating or inhibiting genes that control their top candidate proteins in the hiPS cell-derived neurons. Finally, they will validate the findings in mice.

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"By the end of the project, we hope to narrow down our list to just a few target genes or proteins that protect or restore neuronal health when we activate or inhibit them in live mice with the apoE4 gene," Swaney said. "They could then be explored as potential targets for Alzheimer's treatment in humans."

New Hope for Alzheimer's Disease

Mahley and Swaney already have some ideas about where this work may lead. Earlier this year,they publishedevidence that apoE4 broadly impacts the mitochondriaorganelles that produce the energy that powers a celland perturbs normal energy production.

"Anything could be a target at this point, but I'm particularly interested in the possibility of small-molecule drugs that could protect mitochondria from toxic apoE4 fragments," Mahley said.

Still, mitochondria are just one aspect of the bigger picture. Mahley suspects that what we call "Alzheimer's disease" is actually a collection of related conditions with different underlying causes for different patients.

"Ultimately, I think the treatment of Alzheimer's disease will be similar to the treatment of high blood pressure, in that two, three, sometimes four drugs are needed to control the disorder," he said. "So, we may need a mitochondrial protector, we may need a drug that will correctapoE4's shapeso that it is more like apoE3, and more."

Understanding the complex effects of apoE4as well as the other Alzheimer's disease-associated factorsbeing explored at Gladstonecould one day enable just such a comprehensive approach.

Media Contact:Megan McDevittmegan.mcdevitt@gladstone.ucsf.edu415.734.2019

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team-of-researchers-who-received.jpg Team of Researchers who Received the Grant Gladstone Senior Investigator and President Emeritus Bob Mahley (center) will collaborate with the director of the Gladstone Mass Spectrometry Facility, Danielle Swaney (left), and Senior Investigator Nevan Krogan (right) to uncover the mechanisms of apoE4 toxicity in Alzheimer's disease.

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Gladstone Scientists Funded by NIH to Dive Deep Into ApoE4's Role in Alzheimer's Disease - Yahoo Finance

Innovation in the treatment of COPD – Health Europa

OmniSpirant Limited are a leading European biotech startup company with ambitions to change the paradigm of treatment for respiratory disease. Chronic Obstructive Pulmonary Disease (COPD) is an umbrella term used to describe progressive lung diseases including emphysema, chronic bronchitis, and refractory (non-reversible) asthma. This disease is characterised by increasing breathlessness, frequent chest infections and persistent wheezing. COPD currently cannot be cured or fully reversed.

This debilitating disease today has a solution, developed by OmniSpirant, as we explain below. Until now, the current COPD therapeutics market has lacked any effective disease modifying treatments and the clinical stage pipeline is weak, given the massive disease prevalence; COPD is arguably the disease with the most severely unmet medical and patient needs.

Smoking is indeed the primary cause of this devastating disease, but 15-20% of COPD cases are due to exposures to occupational dust, chemicals, vapours or other airborne pollutants in the workplace. Air pollution is also a likely and underappreciated driver of the growth of the disease and declining lung function in COPD is strongly associated with ageing.

COPD affects up to 500 million patients globally and is the worlds fourth leading cause of death. This dire situation is projected to worsen with COPD becoming the third leading cause of death globally in 2030 and the leading cause of hospitalisations in the industrialised world. COPD is classified as a priority disease by the EU and WHO as it is the only leading cause of death that is rising in prevalence globally. The burden of this chronic respiratory disease is growing rapidly, fuelled by an ageing demographic, persistent smoking habits, and air pollution.

A recent study has estimated that air pollution may be a factor in as many as 47,000 COPD deaths per annum across the 28 EU Member States. Epidemiologic studies have found a measured prevalence of COPD in Europe of between 4% and 10% of adults (European COPD Coalition). However, COPD is widely undiagnosed and untreated especially in its early stages, so the actual prevalence may be higher. New therapies that can slow disease progression desperately need to be developed.

The disease costs tens of billions of euros annually to healthcare payers in reimbursement for largely ineffective pharmacological and medical interventions. In the key United States market, COPD is responsible for USD $72bn (~65bn) per year in direct healthcare expenditures. In the EU, estimated spending on inpatient, outpatient and pharmaceuticals exceeds 10bn per year and productivity losses are estimated at 28.5bn year.

The disease also causes an estimated 300,000 premature deaths in the EU annually (European Respiratory Society). These startling figures are forecast to rise dramatically as the disease prevalence is set to rise sharply.

Current COPD treatments do not include an effective disease modifying therapy which can reduce the exacerbation of symptoms and/or slow down COPD from progressing and worsening. State of the art therapies for COPD consists of combinations of oral, injected or inhaled bronchodilators, anti-muscarinics, corticosteroids, anti-inflammatories, and antibiotics, all of which are used to treat symptoms and reduce exacerbations of COPD with only modest results.

Except for a small minority of Alpha one Antitrypsin (AAT) deficient COPD patients (five in 10,000 carry the mutation responsible for AAT deficiency on both chromosomes), there are no available therapies which modulate disease progression. AAT is a protein that protects the lungs from the destructive actions of common illnesses and exposures, particularly tobacco smoke.

Furthermore, the COPD pipeline is also devoid of disease modifying treatments. The COPD pipeline is full of incremental advances on existing mainstay therapies which merely treat disease symptoms and do not target the root causes of the disease. There are a few innovative therapies in development but a small molecule or biologic agent such as a monoclonal antibody (or even combinations of several of these agents) are highly unlikely to provide a curative or even therapeutically useful intervention in a complex disease like COPD.

OmniSpirant believe that the solution to the COPD epidemic can be found in the new era of advanced therapeutics by combining several technological advances in the fields of cell culturing, genetic engineering and their innovative exosome technology platform. OmniSpirant are developing inhaled bioengineered exosome therapeutics, delivered by a tailored aerosol delivery method based on vibrating mesh nebuliser technology.

In the first instance, the presenting problem is that patients have established lung damage and an increased risk of developing lung cancer (independent of smoking history). OmniSpirant believe that microRNA/mRNA engineered stem cell exosomes can provide powerful anti-inflammatory and regenerative effects and also reduce the risk of patients developing lung malignancies.

Exosomes are naturally produced by cells and recent research highlights the vast potential of stem cell exosomes as transformative regenerative medicines. Stem cell exosomes have shown great regenerative potential in animal models of COPD by stimulation of repair mechanisms and reversing damage to the lung. Stem cells have also shown some promising results in COPD clinical trials.

Donor (Allogeneic) MSCs delivered intravenously in repeat-dose clinical trials for COPD (Prochymal Osiris Therapeutics) were found to be safe and well tolerated and reduced systemic inflammation, but no significant improvements in lung function were observed. We believe that the use of exosomes, as the therapeutic essence of stem cells, delivered by the inhaled route of administration will be capable of far greater efficacy by delivering far higher doses of exosomes directly to the affected lung tissues than intravenous delivery while typically only requiring about 1% of the overall dose. Furthermore, our exosomes will have enhanced delivery (via proprietary surface engineering) and are also bioengineered to enhance efficacy.

OmniSpirants novel technology platform is capable of delivering high doses of these exosomes across the mucus barrier and through cell membranes to deliver the therapeutic payload directly into the diseased lung cells. Such delivery has proven problematic for competing gene transfer technologies because the mucus in the lungs is a barrier that traps the carriers used to deliver gene therapies such as nanoparticles and viral vectors. These trapped gene therapy carriers are mostly cleared from the mucus layer before they can penetrate into the underlying cells and introduce their genetic cargo.

The use of exosomes overcomes other issues associated with viral and non-viral vectors which include the generation of therapy-inactivating host immune responses and poor ability to cross cell membranes. Furthermore, traditional gene transfer vectors may be immunogenic and elicit adverse inflammatory responses.

OmniSpirants solution is a proprietary method of surface engineering exosomes so they can efficiently penetrate the protective mucus barrier and enter into the underlying cells. These stem cell exosomes are therapeutic (regenerative, anti-inflammatory, antimicrobial and antifibrotic), non-immunogenic, and can be tailored via genetic modification of the parent stem cells to create ideal inhaled gene therapy vectors for any lung disease.

The surface engineered exosomes have demonstrated 100% mucus penetration and target cell uptake in the gold standard in vitro model (well-differentiated bronchial epithelial cells in air liquid interface culture), which is game changing compared with the state of the art viral vectors which can achieve only 30% of cells at best. We believe that the enhanced delivery of stem cell exosomes can translate the promising regenerative effects witnessed in various animal models of inflammatory lung diseases into the clinic.

To treat COPD, our approach is to genetically modify the stem cells so that they produce exosomes carrying carefully selected nucleic acids which are tailored for treating the underlying causes of COPD, which has been linked to gene expression and cellular senescence. The genetic element to COPD runs much deeper than just AAT deficiency.

Abnormalities in scores of genes have been clearly shown to increase or decrease the risk of developing COPD and perturbed gene expression is apparent in hundreds of disease associated genes. MicroRNAs (miRNAs) are a recently discovered class of non-coding RNAs that play key roles in the regulation of gene expression and more than 2,000 miRNAs have been identified in the human genome to date. The fact that each miRNA has the ability to target multiple genes within a pathway makes miRNAs one of the most abundant classes of regulatory genes in humans, regulating up to 30% of human protein coding genes.

MiRNAs have been widely shown to be dysregulated in the affected lung tissues of COPD patients which makes an inhaled gene therapy a highly promising approach for treating COPD. Such a gene therapy could effectively modulate the disease altered microRNAs (and their target genes) to halt or even reverse the disease. Recent advances in cell culturing techniques, isolation of exosomes and proprietary cell engineering technologies hold the promise to bring this therapy to the afflicted masses. The BOLD project estimates that there are currently 36 million patients in the EU and US alone with GOLD Stage 2 disease or higher; we need to act quickly as this figure is set to rise dramatically in the coming decade.

OmniSpirant are currently seeking investors or partners to fund the preclinical development of OS002 and anticipate that clinical studies can be initiated within approximately four years an impactful investing opportunity as the rising prevalence of COPD means that by 2030 there may be over 4.5 million deaths annually worldwide and COPD is predicted to be the leading cause of hospitalisation. Lets work together to change those grim statistics.

OmniSpirant and their consortium partners were awarded a 9.3m Irish government grant award (Disruptive Technologies Innovation Fund) in December 2019 to advance the development of their novel COPD gene therapy.*

OmniSpirant have received funding from Horizon 2020, ReSpire, Grant agreement ID: 855463 and have been accelerated by EIT Health.

Gerry McCauleyCEOOmniSpirant Ltd+353 876306538gmccauley@omnispirant.comwww.omnispirant.com

Please note, this article will appear in issue 12 ofHealth Europa Quarterly, which will be available to read in February 2020.

Read more from the original source:
Innovation in the treatment of COPD - Health Europa