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Roche to present results of first prospective trial using blood-based next generation sequencing which successfully identifies people for treatment…

Posted: October 5, 2019 at 4:42 am

Basel, 30 September 2019 - Roche (SIX: RO, ROG; OTCQX: RHHBY) will today announce positive results from a single-arm cohort of the Phase II/III Blood First Assay Screening Trial (BFAST), the first prospective study to use only blood-based next generation sequencing (NGS) to detect specific fusions with the aim of selecting treatment for people with advanced non-small cell lung cancer (NSCLC), without the need for tissue biopsy. Results from the anaplastic lymphoma kinase (ALK) cohort will be presented at the European Society for Medical Oncology (ESMO) 2019 Congress on Monday 30 September 2019, from 9:15 - 9:30 am CEST (Abstract LBA81 PR), and were also part of the official ESMO press programme.

Obtaining tumour tissue for biomarker testing can be a challenge in many people with cancer and, as a result, some may not receive optimal treatment for their disease, said Sandra Horning, MD, chief medical officer and head of Global Product Development. BFAST is the first trial to show that by using a blood-based next-generation diagnostic, it is possible to identify the ALK mutation in people with non-small cell lung cancer using a blood draw alone, which means that more people could potentially benefit from Alecensa.

Foundation Medicine is pleased to partner with Roche on this study, a first-of-its-kind, pivotal trial that directly demonstrates the clinical utility of using our comprehensive blood-based assay, FoundationOne Liquid, to detect specific fusions and match NSCLC patients with first-line treatment, said Brian Alexander, MD, chief medical officer of Foundation Medicine. Validated and comprehensive liquid biopsy tests are critical to help physicians find the best possible treatment approach for patients with advanced cancer and for whom tissue testing isnt feasible. Identifying ALK fusions can be particularly challenging and these data demonstrate that FoundationOne Liquid can accurately predict which patients can respond to therapy.

The BFAST study used FoundationOne Liquid, Foundation Medicines comprehensive liquid biopsy test, which detects the four main classes of genomic alterations, microsatellite instability (MSI) and select fusions including ALK in circulating tumour DNA (ctDNA) from a blood draw. These data demonstrate that the FoundationOne Liquid assay can help to test and identify a broader population of people with advanced NSCLC who may benefit from Alecensa (alectinib), for whom current diagnostic tests are not suitable, such as for those who cannot provide tissue samples due to insufficient or absent tumour tissue or where tissue diagnostics are not available, and validate the clinical utility of blood-based NGS as an additional method to inform clinical decision-making in ALK-positive NSCLC.

In the study, 87.4% (95% CI: 78.5-93.5) of people with advanced NSCLC who were identified by the FoundationOne Liquid biopsy assay to have ALK fusions had a confirmed response to treatment with Alecensa (overall response rate; ORR) as measured by the investigator per Response Evaluation Criteria in Solid Tumours (RECIST v1.1). This is consistent with the ORR for Alecensa observed in the pivotal Phase III ALEX trial, which identified people using tissue-based testing. When measured using an Independent Review Facility per RECIST v1.1, the confirmed ORR was numerically higher at 92.0% (95% CI: 84.1-96.7). Median progression free-survival (PFS) and duration of response (DoR) were not reached after a median follow-up of 12.6 months. The safety profile of Alecensa was consistent with prior clinical trials and post-marketing experience, with no new safety signals observed.

About the BFAST Study BFAST (Blood First Assay Screening Trial; NCT03178552) is a Phase II/III global, multi-centre, open label, multi-cohort study evaluating the safety and efficacy of targeted therapies or immunotherapies as single agents or in combination in people with unresectable, advanced or metastatic NSCLC determined to harbour oncogenic somatic mutations or be tumour mutational burden (TMB) positive as identified by blood-based NGS ctDNA assays. The Alecensa ALK-positive cohort is the first to readout, with other cohorts due to follow. The primary endpoint for the Alecensa ALK-positive cohort of the BFAST study is confirmed investigator (INV)-assessed ORR. Secondary endpoints include: independent review facility (IRF)-assessed ORR, DoR (INV and IRF), PFS (INV and IRF), overall survival (OS) and safety.

About AlecensaAlecensa (RG7853/AF-802/RO5424802/CH5424802) is a highly selective, CNS active, oral medicine created at Chugai Kamakura Research Laboratories and is being developed for people with NSCLC whose tumours are identified as ALK-positive. ALK-positive NSCLC is often found in younger people who have a light or non-smoking history. It is almost always found in people with a specific type of NSCLC called adenocarcinoma. Alecensa is now approved in 83 countries as an initial (first-line) treatment for ALK-positive, metastatic NSCLC, including in the US, Europe, Japan and China.

About Foundation Medicine Foundation Medicine is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient's unique cancer. The company, a member of the Roche Group, offers a full suite of comprehensive genomic profiling tests to identify the molecular alterations in a patient's cancer and match them with relevant targeted therapies, immunotherapies and clinical trials. Foundation Medicines molecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer.

For more information, please visit http://www.foundationmedicine.com or follow Foundation Medicine on Twitter (@FoundationMedicineATCG).

About Roche in lung cancerLung cancer is a major area of focus and investment for Roche, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have five approved medicines to treat certain kinds of lung cancer and more than ten medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About RocheRoche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve peoples lives. The combined strengths of pharmaceuticals and diagnostics under one roof have made Roche the leader in personalised healthcare a strategy that aims to fit the right treatment to each patient in the best way possible.

Roche is the worlds largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management.

Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. More than thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Moreover, for the eleventh consecutive year, Roche has been recognised as one of the most sustainable companies in the Pharmaceuticals Industry by the Dow Jones Sustainability Indices (DJSI).

The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2018 employed about 94,000 people worldwide. In 2018, Roche invested CHF 11 billion in R&D and posted sales of CHF 56.8 billion. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit http://www.roche.com.

All trademarks used or mentioned in this release are protected by law.

Roche Group Media RelationsPhone: +41 61 688 8888 / e-mail: media.relations@roche.com- Nicolas Dunant (Head)- Patrick Barth- Ulrike Engels-Lange- Daniel Grotzky- Karsten Kleine- Nathalie Meetz- Barbara von Schnurbein

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Keeping the Gene Expression of Sex Chromosomes in Balance – Technology Networks

Posted: October 5, 2019 at 4:42 am

Researchers at Karolinska Institutet in Sweden have uncovered a chromosome-wide mechanism that keeps the gene expression of sex chromosomes in balance in our cells. The findings shed light on molecular reasons for early miscarriage and could be important for the emerging field of regenerative medicine. The study is published in Nature Structural and Molecular Biology.

The genes in our cells are packaged into 23 large units of DNA called chromosomes. The sex chromosomes, X and Y, differ from all other chromosomes in that they are only present as one active copy per cell instead of two. This renders a copy-number imbalance between genes located on sex chromosomes and the rest of our genome. Now researchers at Karolinska Institutet have figured out how our cells manage to double the expression of X-chromosome genes to achieve balance.

By examining gene expression dynamics in fine detail in female and male embryonic and somatic cells, the researchers found that genes on the X chromosome produced waves of gene products at a faster tempo than other chromosomes.

"The X chromosome generates 'bursts' of gene expression at higher rate that other chromosomes, pointing to the involvement of special DNA elements called enhancers in maintaining an elevated X-chromosome expression" says Bjrn Reinius, the principal investigator at the Department of Medical Biochemistry and Biophysics, who directed the study.

In female cells, carrying two X chromosomes, the increased tempo established on one X-chromosome copy during the same developmental window in which the second X-copy became inactivated. 'X inactivation' is a previously characterized mechanism that keeps one X chromosome silent in women, resulting in patches of cells expressing either the maternal or paternal copy. Male cells, carrying only one X chromosome, instead maintained a constantly fast rhythm of expression throughout developmental phases and cell types.

"Failure to establish X-chromosome dosage compensation during the early female embryogenesis is lethal and leads to early spontaneous abortion" Reinius says. "With the new knowledge, we better understand how the cells' gene expression network becomes destabilised."

According to the researchers, the findings represent a breakthrough in understanding sex-chromosome gene regulation. Understanding these chromosome-wide mechanisms could also be important in the field of regenerative medicine, since the reprogramming of cells may disturb the X-chromosome dosage balance in a gender-specific manner.

Reference: Larsson, Coucoravas, Sandberg and Reinius. 2019.X-chromosome upregulation is driven by increased burst frequency. Nature Structural and Molecular Biology. DOI: https://doi.org/10.1038/s41594-019-0306-y.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Institute of Human Virology Hosts 21st Annual International Meeting of Top Scientists on Ending the HIV/AIDS Epidemic in America and the Intersection…

Posted: October 5, 2019 at 4:42 am

BALTIMORE--(BUSINESS WIRE)--The Institute of Human Virology (IHV) at the University of Maryland School of Medicine commenced IHV2019 held Thursday, October 3 through Friday, October 4 at the Four Seasons Hotel in Baltimore, Maryland. This year Progress in HIV/AIDS: Challenges in 2020 opened with highlights about the recent plan for "Ending the HIV Epidemic by 2030 with expert opinions by ADM Brett Giroir, MD, Assistant Secretary for Health at the U.S. Department of Health and Human Services (HHS), Anthony Fauci, MD, Director at the National Institute of Allergy and Infectious Diseases (NIAID) and Nora Volkow, MD, Director, National Institute of Drug Abuse (NIDA), among other notable speakers. The Meeting focuses on two critical issues, including leveraging scientific advances in the field of HIV to end the epidemic in America and integrating resources to address the ongoing opioid epidemic and prevent its impact on the lives of HIV-infected patients. The Annual International Meeting attracts hundreds of elite scientists who descend upon Baltimore to share ideas and inspire medical virus research collaborations.

We have known for some time that it is, at least in theory, possible to end the HIV/AIDS epidemic, and I am pleased we are focusing on these efforts in addition to uniquely focusing on the intersection of infectious disease and opioid use disorder, said Robert C. Gallo, MD, the Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-founder and Director of the Institute of Human Virology at the University of Maryland School of Medicine and Co-founder and International Scientific Advisor of the Global Virus Network (GVN). We are grateful to our nations leaders for advancing efforts to end the epidemic. Further, clinicians are uniquely positioned to advance addiction research as many infectious disease patients coming into the clinic are also afflicted with opioid use disorder.

During a gala held this evening, the 2019 IHV Lifetime Achievement Awardees, who are nominated and voted upon by IHV faculty, will be honored.

The 2019 IHV Lifetime Achievement Award for Scientific Contributions will be presented to Warner Greene, MD, PhD, Director, Gladstone Center for HIV Cure Research, Nick and Sue Hellmann Distinguished Professor of Translational Medicine, Founding and Emeritus Director, Gladstone Institute of Virology and Immunology (GIVI). Dr. Greene was a leader in the new field of the molecular biology of all human retroviruses, beginning with HTLV-1, the first discovered human retrovirus back in 1980, by Dr. Gallo and his colleagues, as well as HIV by the mid 1980s. Dr. Greenes research focused on many aspects of the understanding of the biology of the virus, including its molecular biology, its genes and their products how it replicated, how it induced, and other aspects of resistance to infection and the pathogenic mechanisms of how HIV causes disease. In recent years, he has turned his attention towards finding new ways to advance science so that a patient could live a normal life without any drug therapy whatsoever. Warner has also expanded his work to include global health activities in sub-Saharan Africa, and he has mentored more than 130 students and fellows during his career.

Warner Greene is a national treasure in the molecular biology of very important viruses and genes, said Dr. Gallo.

Two deserving individuals will receive the 2019 IHV Lifetime Achievement Award for Public Service.

The first will be presented to The Honorable Kathleen Kennedy Townsend, Director of Retirement Security, Economic Policy Institute, Lt. Governor of Maryland (1995-2003). As Marylands first woman Lt Governor, along with Gov. Parris Glendening, she recruited Dr. Gallo and his colleagues to the State. The Institute has great respect for the Lt. Governor for helping people in need and advancing human health in multiple areas, where she has worked very hard and lent her time. She became one of IHVs early board chairs, is a current IHV Board member and has been a tremendous force in paving the way for the Institutes success here in Maryland. The Lt. Governor previously served as Deputy Assistant Attorney General of the United States, led the fight to make Maryland the firstand onlystate to make service a high school graduation requirement, and has served in numerous other public service roles.

The second will be presented to The Honorable Parris Glendening, President, Smart Growth Americas Leadership Institute, President, Governors Institute on Community Design, Governor of Maryland (1995-2003). Among other important benefits from Governor Glendening, who led the recruitment of Dr. Gallo and his colleagues, Robert Redfield, MD and William Blattner, MD, to form the Institute, it was the Governors personal commitment to their mission, having shared publicly about the death of his brother from AIDS, which brought them closer. In addition, the Governor has a long history of public service, including his current national and international advocacy on smart growth, sustainability, global climate change, land conservation, transit-oriented development and equity. He was previously elected in local positions in the State and served as a professor at the University of Maryland, College Park for 27 years.

For both the Governor and Lt. Governor, we not only honor them with this Lifetime Achievement Award in Public Service because of their vital roles in the formation of the Institute, which never would have happened without them, but also as a public thank you, for their local, national and international service and leadership, said Dr. Gallo.

Since IHVs founding, the Baltimore-based Institute faculty and staff have grown from 50 to more than 300, and the Institute's patient base has grown from just 200 patients to currently more than 5,000 in Baltimore and Washington, DC, and more than 2 million in African and Caribbean nations since 2004. IHV is also internationally renowned for its basic science research, which includes a promising preventive HIV vaccine funded largely by the Bill & Melinda Gates Foundation and, in part, by others including National Institute of Allergy and Infectious Diseases.

For more information, visit http://www.ihv.org.

About the Institute of Human Virology

Formed in 1996 as a partnership between the State of Maryland, the City of Baltimore, the University System of Maryland and the University of Maryland Medical System, IHV is an institute of the University of Maryland School of Medicine and is home to some of the most globally-recognized and world-renowned experts in all of virology. The IHV combines the disciplines of basic research, epidemiology and clinical research in a concerted effort to speed the discovery of diagnostics and therapeutics for a wide variety of chronic and deadly viral and immune disorders - most notably, HIV the virus that causes AIDS. For more information, http://www.ihv.org and follow us on Twitter @IHVmaryland.

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Institute of Human Virology Hosts 21st Annual International Meeting of Top Scientists on Ending the HIV/AIDS Epidemic in America and the Intersection...

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Digital Biopsies: Radiomics and Pathomics Are Important Stops on the Path to Precision Medicine – Cancer Therapy Advisor

Posted: October 5, 2019 at 4:42 am

The goal of finding a cure for cancer was eclipsed long ago by the need to identify and understand the wide variety of cancers and their subtypes, and the need to focus on developing therapies specific to different cancer mechanisms and challenges. With this understanding and the rise of immunotherapy and genomic sequencing, a vast chunk of current cancer research now focuses on finding biomarkers that can predict disease response to certain drugs and guide therapy protocols.

But single biomarkers genomic, molecular, orotherwise can only go so far in predicting responses given the complexity andheterogeneity of individual malignancies and their microenvironments.

The exploding field of genomics is advancing, andresearchers are starting to examine constellations of features that may bettercharacterize disease subtypes on the path to precision medicine, but genomicsalone cannot always distinguish differing phenotypes within cancer subtypes.

Hence, the rise of radiomics and pathomics, whichare fields that take a similar approach to genomics using technology to betterunderstand features of solid tumors.

We have been moving in the latest 15 years froman organ-based cancer treatment to [a] histology-based one, to the most recentprecision medicine, which means that we are going to treat the specificalteration of the tumor independently by the site where [it] arose, Giuseppe Luigi Banna, MD, of the UnitedLincolnshire Hospital Trust in Lincoln, United Kingdom, told Cancer TherapyAdvisor.

Dr Banna and his colleagues recently published apaper exploring the promise of digital biopsy for predicting immunotherapyoutcomes based on radiomics and pathomics.1 Although moleculardeterminants such as PD-1 or PD-L1 expression, and tumor mutational burden(TMB), are already used in clinical practice, these fail in consistency,applicability, or reliability to precisely identify the responding patientsmainly because of their spatial intratumoral heterogeneity, they wrote.

Dr Banna elaborated: The following 3 mainproblems with the current assessment of PD-L1 could be overcome by pathomicsand radiomics: the different platforms used to test it, the possibleinterobserver variability, and the dynamic changes in PD-L1 expression.

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Walking in His Shoes – Curetoday.com

Posted: October 5, 2019 at 4:41 am

A man who received chimeric antigen receptor-T cell therapy shares his firsthand account.

Backer received a diagnosis of diffuse large B-cell lymphoma (DLBCL). It is the most common type of non-Hodgkin lymphoma, which affects nearly 75,000 people mostly men in the United States each year.

Despite multiple rounds of chemotherapy and a stem cell transplant, Backers disease kept relapsing. Then he participated in a clinical trial involving chimeric antigen receptor (CAR)-T cell therapy, which has left him cancer-free for almost three years. With this type of immunotherapy, a patients T cells are removed, altered in a lab and then reinfused in the hope that they will attack cancer cells.

Dr. Frederick L. Locke, a medical oncologist at Moffitt Cancer Center in Tampa, Florida, isco-lead investigator of the pivotal ZUMA-1 trial, which led to the Food and Drug Administration (FDA) approval of the second available CAR-T cell therapy, Yescarta (axicabtagene ciloleucel). During the National Comprehensive Cancer Network 2019 Annual Conference, Locke, Backer and Alix Beaupierre, a transplant nurse coordinator, took a 360-degree look at CAR-T cell therapy.

LIMITED OPTIONSOutcomes in refractory aggressive non-Hodgkin lymphoma are poor, Locke explained. Patientsare often treated upfront with combination chemotherapy, as Backer was. He initially wenton a chemotherapy regimen commonly known as R-CHOP Rituxan (rituximab), cyclophospha- mide, Adriamycin (doxorubicin), Oncovin (vincris- tine) and prednisone. He achieved a complete remission and went back to work.

We can cure up to about 60% of patients with initial chemotherapy, and thats pretty remarkable, Locke said. Unfortunately, 40% of patients either dont respond to chemotherapy or progress.

Backer was among that 40%. He relapsed about a year later and started on a new chemotherapy regimen with a planned autologous stem cell transplant, which would involve removing his own stem cells and later putting them back into his body to help fight the cancer. This treatment plan cures only about 5% of patients, Locke said. Prior to CAR-T cell therapy, more chemotherapy would have been next.

In the United States, two CAR-T therapies are available to patients with certain types of cancer. The first, Kymriah (tisagenlecleucel), was approved in August 2017 for patients up to 25 years old who have acute lymphoblastic leukemia that relapsed or did not go into remission with other treatments. Two months later, the FDA approved Yescarta to treat adult patients with certain types of large B-cell lymphoma who have not responded to or relapsed after at least two other kinds of treatment.In patients with DLBCL, durable responses the length of time that a partial or complete response is observed because of treatment have been seen in 40% of patients who received CAR-T cell therapy. We think we can cure about 15% of people, Locke said. We need these patients referred and referred early.

A NUCLEAR BOMBBacker first read about CAR-T cell therapy on clinicaltrials.gov, an online registry of all clinical trials that anyone can access to see what might be enrolling participants. Im the typeof person who needs a plan A and a plan B, Backer said.I received a plan A, but the plan B in the case of the transplant failing was not encouraging.

He reached out to Moffitt Cancer Center Tampa is not far from where he lived in Orlando, Florida to see if he was eligible. He wasnt. In December 2015, Backer went ahead with the stem cell transplant. A few months later,he again relapsed with growths all over his body butthis made his participation in the ZUMA-1 clinical trial possible. Being a participant in a clinical trial is scary and daunting at the same time, he said. I remember sitting there with the transplant coordinator and they handed me a 27-page consent form, and I could barely read page one. Ijust wanted to sign. I was ready to sign anything right then and there.

Although potentially curative, CAR-T cell therapy is not without risk. Patients can develop two serious side effects. Cytokine release syndrome, caused by a large, rapid release of cytokines (small proteins importantin cell signaling) into the blood from immune cells affected by the immunotherapy, can be life-threatening. Neurological events, such as confusion, tremor and seizures, can also occur.

Despite lengthy discussions with his medical teamat Moffitt and reading the consent form, Backer said,he wasnt fully prepared for the coming side effects and recovery when he went forward with CAR-T therapy in June 2016. Thats when the nuclear bomb set off, he said. Within 12 hours of receiving the infusion, he experienced severe chills, violent shaking and a high fever, and also felt certain he was experiencing side effects that were affecting his brain.

About two days after Backer received the reinfusedT cells, the infectious disease team rushed him in for a CT scan. They found no infection and no signs of the cancer.

For me, it was a miracle treatment, Backer said.

Locke has been following patients enrolled in ZUMA-1 for more than two years and said that half are still alive.

BEING PREPAREDBacker admitted that going in with a full understanding of CAR-T cell therapy would have made the experience dramatically different.

After seeing patients and their loved ones in distress, care providers at Moffitt Cancer Center learned to smooth the process, Beaupierre said. For instance, the 27-page document has been broken down into one-page educational handouts and shorter consent forms. The team also created a flow sheet and that grew to a detailed patient calendar. All CAR-T therapy recipients also now have a dedicated nurse and social worker.

In addition to those resources, Backer said, peer-to-peer support would be helpful.

As CAR-T cell therapy continues to evolve and be explored in the treatment of other cancer types, experts are learning more about how it works and how to improve the process.

For Backer, quality of life has changed a bit. Initially, he received blood and platelet transfusions every two weeks for several months following CAR-T cell therapy. Although he is back to work full time, he runs the risk of being exposed to other diseases and viruses. Its always at the back of my mind, he said. I wear a mask and goggles at work but still get sick.

He spends his free time hiking and fishing and feels blessed to still be alive. It worked out for me, and here we are 33 months into this thing, Backer said.

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"I have talked about this treatment for so long… I finally gave in and set up the GoFundMe page. It killed me to have to do it." – Echo…

Posted: October 4, 2019 at 7:49 am

AN ordinary man with ordinary interests, Patrick Keane loves life, even though it has become more of a challenge than ever before.

He cannot play a round of golf or go for a walk by the beach any more. But he doesnt want pity and exudes positivity. So he enjoys soaking in the sea air around Clonea or Garryvoe without stretching his legs.

But reality has a way of crashing through the faade at times, no matter how strong you are.

For Patrick, it can be when he wakes up and cannot feel his legs, or loses his train of thought, or misses his mouth when trying to eat because he cannot feel the spoon in his hand. Or if he gets out of bed and falls and screams at himself, Just get up will ya, ya fool!

But the man known as Pa to his friends, or Patch to his mother Margaret, brother Paul and sisters Yvonne and Elaine, dusts himself down, drags himself back to an upright position and goes about taking on the day in as fearless a fashion as possible, given what he must encounter now and the knowledge of what lies ahead.

Multiple sclerosis affects the central nervous system, the brain and the spine, and while the rate of degeneration differs for all, there is no escaping the degeneration. Ireland has 8,000 sufferers with apparently no cure.

Patrick, who was diagnosed in January, 2009, is not without hope however. A doctor, Denis Federenko, has been providing stem cell transplants to people from all over the world at the AA Maximov Hospital in Moscow, with some success, by wiping out the faulty immune system with drugs used to treat cancer and replacing it with stem cells taken from the patient.

Irish comedian, Stephen Garland is one who underwent treatment in November, 2016, having been told he was around six months away from being confined to a wheelchair.

He returned home just before Christmas that year and has thrived since, even writing a show about his journey to Russia and back.

Garland brought his creation, Post-Disposed, back to the world-renowned Edinburgh Fringe Festival in August, confirming his continuing improved health.

The treatment costs between 50,000 and 60,000 including aftercare and other expenses. It can be hard to ask for help but so many people have extended a hand to Patrick, without ever being asked. People Patrick doesnt know from Adam or Eve have even contributed to his cause and it moves him to tears.

Time is against the Corkman however, because if his condition exceeds 6.5 on a scale of 0-8, he will not be taken on. At present, he is between 5.5 and 6, and has been accepted, but clearly the treatment must take place sooner rather than later.

To that end, a Breakfast With The Stars event is taking place at The Park Hotel, Dungarvan on Thursday, October 10. Tipperarys All-Ireland-winning manager, Liam Sheedy and multiple champion jockey Davy Russell will regale patrons with stories from their careers, prompted by MC Marty Morrissey.

All proceeds will go towards funding Patricks treatment and ancillary expenses. Ticket purchasing details are below.

Here is more about Patricks story...

************

LAYLA walks into the family home in Ballinroad, just outside Dungarvan. It was Patrick who named her, after the Eric Clapton song that he happened to be listening to when the family were discussing what to call the now 12-year-old dog.

Music is a boon, a real infusion of energy, pumping the blood, making him feel like he could jump out of his skin and dance like the old days. He cant but that burst of adrenaline is a godsend.

I have the car adapted with hand controls, Patrick explains. I dont use my feet for driving. Push and pull the lever in the car.

On a Sunday morning I love nothing better, especially when I am down at home. Head down the coast road to Tramore, listen to a bit of music.

I would listen to absolutely anything. I am influenced by dads taste in music. All the older stuff, 70s, 80s rock music kind of stuff. You could find me listening to dance music two minutes later. Once it has a beat I couldnt care less.

Patricks dad, Richie Keane, was a hard worker, who was brilliant with his hands and especially with cars. And all his life he had a smaller shadow. The son looked up to the father like he was Superman.

When he was sick and on his last legs, talking through the window from the house he taught me how to take the sump off my car because it was cracked and leaking oil. He was able to guide me through it without looking at it, word for word.

I restored a Jeep that he left when he passed away. It was a 1983, same age as myself, Mercedes jeep. Very rare, like hens teeth. Restored it to about 25,000 to 30,000 worth.

I had to sell it. I couldnt drive it anymore because the leg was so bad. That was hard. That was the last connection. It was something I had to remember him by. The day I saw that go out the drive was tough.

Richie died in November, 2008, around the time of Patricks 25th birthday. Richies mother passed away two weeks later. Patrick was diagnosed with MS in January, 2009. Already a celiac and diabetic, he was accustomed to restrictions and putting up with things. This was a different stratosphere though.

It began with losing his balance and the development of numbness down his right side.

I went to the doctor, and I think, by the look on his face, he knew there was something not right. He sent me to Ardkeen (Hospital) and I got checked out. They had me in isolation for about a week. Then I was told it was MS.

I didnt know what it was but it was something I heard from a conversation when I was younger, That poor fella has MS. I didnt know I would end up the way I am now.

I have friends since that have been diagnosed after me that I have gotten to know from reaching out. There are a couple of them in a wheelchair. As it progresses, that is where you are heading. But there is a gentleman up the road and he must have it for 20-something years. Unless someone told you, you wouldnt know he has MS.

Part of the difficulty of dealing with MS is that no two cases are alike. Keeping active, having physiotherapy regularly and working are advantages and Patrick has not declined as quickly as others because of that.

But he has hit the secondary stage, where there are cognitive problems and, in particular, his short-term memory is affected.

People say to me, do you get pain with it? I dont know what new pain or old pain is. I just get on with. I have my days where I whinge and moan and cry. God knows I have them. But there is people out there worse off. I have what I have.

It could get worse. Now that it is gone to progressive MS, it probably will. When or how long? Who knows?

It is a horrible disease, there is no two ways. But you get up, get on with it, and do what you can.

He went to Australia not long after the diagnosis. It was a real gesture of defiance, one that probably scared his mother but he knew too that it might well be a case of now or never.

A blocklayer by trade, Patrick eventually had to give that up as his coordination worsened and he nearly fell off a roof. He is on crutches now for three years and would not be able to catch a football if you threw it at him. He wears a leg cast too, to reduce the instances of tripping himself up, without eradicating them totally. He has a mobility scooter.

A 35-year-old man doesnt dream about a mobility scooter, he wants a flash sports car. But it allowed me to go down to the Greenway for the first time. That was nice, to be on the Greenway, to be out, and see the whole lot of it, it was lovely. But watching other people cycle off down killed me.

My two nephews were out the front playing soccer. I used to do the exact same thing. They were saying Patrick, are you coming out to play? I said I would love to but that gets you. Its the simple little things.

Katie, my partner, I dont know where I would be without her. My mam, the girls and my brother, they are fantastic. They have been with me since the start of it.

I decided I want to be independent. If I didnt have the car I dont know what I would be doing. That is my freedom. I can get into the car, go to the shop for coffee. I will get there. I will get the same place as anyone else will, but it will take me longer.

He lives in Cork with Katie and her son Aaron, and works for Voxpro, who have been tremendously supportive. If he were housebound, he would wither.

I am an outgoing guy. I would chat away, waffle on about anything for hours on end. But you take that away I dont know have I changed since the diagnosis.

I have tried to remain as positive as possible but sometimes its hard. Simple little things you take for granted. Just run out there to get the clothes off the line. Now I have had to get handrails put into the house so that I can get up when I trip and fall.

I would wake in the mornings and the legs are like jelly. They shake, you cant control it, you let them shake out and that could be for 20 or 30 seconds. Real spasticity and stiffness in the legs. With the heat during the summer, I sat in the car with the air con on. I would be good for doing weather forecasta. I know what its like when I wake up in the morning, ever before the curtains are pulled. I feel it in my body.

He has been trawling for potential treatments, along with his medical team. Dr Federenkos work stands up to inspection. Stopping the MS in its tracks without the need for further medication would be a tantalising prospect.

Reversing the effects is something he dare not even contemplate, though the treatment has had that effect in Garland and many others.

Being given the green light, after Dr Federenko reviewed his case and medical records, was like an infusion in itself. Patrick details every step of the treatment and though it sounds daunting, it isnt compared to the alternative.

He set up the GoFundMe page (https://www.gofundme.com/f/stop-ms-progression-with-stem-cells-transplant) and was staggered by the reaction. Meanwhile, the local community has rallied, as have his work colleagues and friends, organising fund-raiser after fund-raiser. People he didnt know had events. He finds it hard to process.

To ask for someones help, it is a sign that you are not able. I have talked about this treatment for so long and I got so bad in my legs and balance and everything, I finally gave in and set up the GoFundMe page. It killed me to have to do it.

There was a donation yesterday on GoFundMe from Jamaica. I dont know the person but they found it in their heart to say, There you go. People said to me, Sorry I cant give you too much, I want to give you more. If it is a euro or 20 cent, it could be that 20 cent or euro that gets me over the line.

Whatever happens, he will not give up because it is what he learned when he was Richies shadow: It is instilled in me from dad, I would always have looked up to him. Even now, since he has passed away, I would always say to myself, What would he do? Would he have approved of that? He would always say to stick at something until you get it. If you are going to start something, do it. Just dont walk away from it.

Breakfast With The Stars, featuring Tipperary manager Liam Sheedy, one of the all-time greats of National Hunt racing Davy Russell and RTs Marty Morrissey, takes place at The Park Hotel on Thursday, October 10. To book a table of 10 for 1000 contact Michael Ryan (087 2585299) or The Local Bar (058 41854).

Donations can also be made to Patrick Keanes GoFundMe pagehttps://www.gofundme.com/f/stop-ms-progression-with-stem-cells-transplant

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"I have talked about this treatment for so long... I finally gave in and set up the GoFundMe page. It killed me to have to do it." - Echo...

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I hope treatment will stop Multiple Sclerosis in its tracks – Echo Live

Posted: October 4, 2019 at 7:49 am

AN ordinary man with ordinary interests, Patrick Keane loves life, even though it has become more of a challenge than ever before.

He cannot play a round of golf or go for a walk by the beach any more. But he doesnt want pity and exudes positivity. So he enjoys soaking in the sea air around Clonea or Garryvoe without stretching his legs.

But reality has a way of crashing through the faade at times, no matter how strong you are.

For Patrick, it can be when he wakes up and cannot feel his legs, or loses his train of thought, or misses his mouth when trying to eat because he cannot feel the spoon in his hand. Or if he gets out of bed and falls and screams at himself, Just get up will ya, ya fool!

But the man known as Pa to his friends, or Patch to his mother Margaret, brother Paul and sisters Yvonne and Elaine, dusts himself down, drags himself back to an upright position and goes about taking on the day in as fearless a fashion as possible, given what he must encounter now and the knowledge of what lies ahead.

Multiple sclerosis affects the central nervous system, the brain and the spine, and while the rate of degeneration differs for all, there is no escaping the degeneration. Ireland has 8,000 sufferers with apparently no cure.

Patrick, who was diagnosed in January, 2009, is not without hope however. A doctor, Denis Federenko, has been providing stem cell transplants to people from all over the world at the AA Maximov Hospital in Moscow, with some success, by wiping out the faulty immune system with drugs used to treat cancer and replacing it with stem cells taken from the patient.

Irish comedian, Stephen Garland is one who underwent treatment in November, 2016, having been told he was around six months away from being confined to a wheelchair.

He returned home just before Christmas that year and has thrived since, even writing a show about his journey to Russia and back.

Garland brought his creation, Post-Disposed, back to the world-renowned Edinburgh Fringe Festival in August, confirming his continuing improved health.

The treatment costs between 50,000 and 60,000 including aftercare and other expenses. It can be hard to ask for help but so many people have extended a hand to Patrick, without ever being asked. People Patrick doesnt know from Adam or Eve have even contributed to his cause and it moves him to tears.

Time is against the Corkman however, because if his condition exceeds 6.5 on a scale of 0-8, he will not be taken on. At present, he is between 5.5 and 6, and has been accepted, but clearly the treatment must take place sooner rather than later.

To that end, a Breakfast With The Stars event is taking place at The Park Hotel, Dungarvan on Thursday, October 10. Tipperarys All-Ireland-winning manager, Liam Sheedy and multiple champion jockey Davy Russell will regale patrons with stories from their careers, prompted by MC Marty Morrissey.

All proceeds will go towards funding Patricks treatment and ancillary expenses. Ticket purchasing details are below.

Here is more about Patricks story...

************

LAYLA walks into the family home in Ballinroad, just outside Dungarvan. It was Patrick who named her, after the Eric Clapton song that he happened to be listening to when the family were discussing what to call the now 12-year-old dog.

Music is a boon, a real infusion of energy, pumping the blood, making him feel like he could jump out of his skin and dance like the old days. He cant but that burst of adrenaline is a godsend.

I have the car adapted with hand controls, Patrick explains. I dont use my feet for driving. Push and pull the lever in the car.

On a Sunday morning I love nothing better, especially when I am down at home. Head down the coast road to Tramore, listen to a bit of music.

I would listen to absolutely anything. I am influenced by dads taste in music. All the older stuff, 70s, 80s rock music kind of stuff. You could find me listening to dance music two minutes later. Once it has a beat I couldnt care less.

Patricks dad, Richie Keane, was a hard worker, who was brilliant with his hands and especially with cars. And all his life he had a smaller shadow. The son looked up to the father like he was Superman.

When he was sick and on his last legs, talking through the window from the house he taught me how to take the sump off my car because it was cracked and leaking oil. He was able to guide me through it without looking at it, word for word.

I restored a Jeep that he left when he passed away. It was a 1983, same age as myself, Mercedes jeep. Very rare, like hens teeth. Restored it to about 25,000 to 30,000 worth.

I had to sell it. I couldnt drive it anymore because the leg was so bad. That was hard. That was the last connection. It was something I had to remember him by. The day I saw that go out the drive was tough.

Richie died in November, 2008, around the time of Patricks 25th birthday. Richies mother passed away two weeks later. Patrick was diagnosed with MS in January, 2009. Already a celiac and diabetic, he was accustomed to restrictions and putting up with things. This was a different stratosphere though.

It began with losing his balance and the development of numbness down his right side.

I went to the doctor, and I think, by the look on his face, he knew there was something not right. He sent me to Ardkeen (Hospital) and I got checked out. They had me in isolation for about a week. Then I was told it was MS.

I didnt know what it was but it was something I heard from a conversation when I was younger, That poor fella has MS. I didnt know I would end up the way I am now.

I have friends since that have been diagnosed after me that I have gotten to know from reaching out. There are a couple of them in a wheelchair. As it progresses, that is where you are heading. But there is a gentleman up the road and he must have it for 20-something years. Unless someone told you, you wouldnt know he has MS.

Part of the difficulty of dealing with MS is that no two cases are alike. Keeping active, having physiotherapy regularly and working are advantages and Patrick has not declined as quickly as others because of that.

But he has hit the secondary stage, where there are cognitive problems and, in particular, his short-term memory is affected.

People say to me, do you get pain with it? I dont know what new pain or old pain is. I just get on with. I have my days where I whinge and moan and cry. God knows I have them. But there is people out there worse off. I have what I have.

It could get worse. Now that it is gone to progressive MS, it probably will. When or how long? Who knows?

It is a horrible disease, there is no two ways. But you get up, get on with it, and do what you can.

He went to Australia not long after the diagnosis. It was a real gesture of defiance, one that probably scared his mother but he knew too that it might well be a case of now or never.

A blocklayer by trade, Patrick eventually had to give that up as his coordination worsened and he nearly fell off a roof. He is on crutches now for three years and would not be able to catch a football if you threw it at him. He wears a leg cast too, to reduce the instances of tripping himself up, without eradicating them totally. He has a mobility scooter.

A 35-year-old man doesnt dream about a mobility scooter, he wants a flash sports car. But it allowed me to go down to the Greenway for the first time. That was nice, to be on the Greenway, to be out, and see the whole lot of it, it was lovely. But watching other people cycle off down killed me.

My two nephews were out the front playing soccer. I used to do the exact same thing. They were saying Patrick, are you coming out to play? I said I would love to but that gets you. Its the simple little things.

Katie, my partner, I dont know where I would be without her. My mam, the girls and my brother, they are fantastic. They have been with me since the start of it.

I decided I want to be independent. If I didnt have the car I dont know what I would be doing. That is my freedom. I can get into the car, go to the shop for coffee. I will get there. I will get the same place as anyone else will, but it will take me longer.

He lives in Cork with Katie and her son Aaron, and works for Voxpro, who have been tremendously supportive. If he were housebound, he would wither.

I am an outgoing guy. I would chat away, waffle on about anything for hours on end. But you take that away I dont know have I changed since the diagnosis.

I have tried to remain as positive as possible but sometimes its hard. Simple little things you take for granted. Just run out there to get the clothes off the line. Now I have had to get handrails put into the house so that I can get up when I trip and fall.

I would wake in the mornings and the legs are like jelly. They shake, you cant control it, you let them shake out and that could be for 20 or 30 seconds. Real spasticity and stiffness in the legs. With the heat during the summer, I sat in the car with the air con on. I would be good for doing weather forecasta. I know what its like when I wake up in the morning, ever before the curtains are pulled. I feel it in my body.

He has been trawling for potential treatments, along with his medical team. Dr Federenkos work stands up to inspection. Stopping the MS in its tracks without the need for further medication would be a tantalising prospect.

Reversing the effects is something he dare not even contemplate, though the treatment has had that effect in Garland and many others.

Being given the green light, after Dr Federenko reviewed his case and medical records, was like an infusion in itself. Patrick details every step of the treatment and though it sounds daunting, it isnt compared to the alternative.

He set up the GoFundMe page (https://www.gofundme.com/f/stop-ms-progression-with-stem-cells-transplant) and was staggered by the reaction. Meanwhile, the local community has rallied, as have his work colleagues and friends, organising fund-raiser after fund-raiser. People he didnt know had events. He finds it hard to process.

To ask for someones help, it is a sign that you are not able. I have talked about this treatment for so long and I got so bad in my legs and balance and everything, I finally gave in and set up the GoFundMe page. It killed me to have to do it.

There was a donation yesterday on GoFundMe from Jamaica. I dont know the person but they found it in their heart to say, There you go. People said to me, Sorry I cant give you too much, I want to give you more. If it is a euro or 20 cent, it could be that 20 cent or euro that gets me over the line.

Whatever happens, he will not give up because it is what he learned when he was Richies shadow: It is instilled in me from dad, I would always have looked up to him. Even now, since he has passed away, I would always say to myself, What would he do? Would he have approved of that? He would always say to stick at something until you get it. If you are going to start something, do it. Just dont walk away from it.

Breakfast With The Stars, featuring Tipperary manager Liam Sheedy, one of the all-time greats of National Hunt racing Davy Russell and RTs Marty Morrissey, takes place at The Park Hotel on Thursday, October 10. To book a table of 10 for 1000 contact Michael Ryan (087 2585299) or The Local Bar (058 41854).

Donations can also be made to Patrick Keanes GoFundMe pagehttps://www.gofundme.com/f/stop-ms-progression-with-stem-cells-transplant

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I hope treatment will stop Multiple Sclerosis in its tracks - Echo Live

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Gene therapy stocks have taken a beating. Their recovery may be slow – BioPharma Dive

Posted: October 4, 2019 at 7:47 am

The honeymoon period for gene therapy developers was short-lived. Shares of at least 26 are trading lower now than they were a year ago, amounting to roughly $18 billion in lost market value.

Relief may not come soon, either. Analysts suspect investors aren't just looking for promising safety and efficacy data anymore;they want to know how companies intend to make money off these treatments. Most don't have answers to that question yet.

"There's this phase, not just in gene therapy, but in most companies or technologies, where it's all exuberance and development," said Tyler Van Buren, an analyst at Piper Jaffray. "A lot of that can end once rubber hits the road and you have to launch a product."

Bluebird bio is having this problem. The Boston biotech's share price is down 41% from a year ago and 26% since mid-June, when executives said the European launch of its Zynteglo gene therapy would be pushed back from 2019 to 2020.

Mani Faroohar of investment bank SVB Leerink argues the delay has dimmed investor confidence in smaller biotechs working on "transplant" gene therapies like Zynteglo, which treats a blood disorder known as beta-thalassemia by harvesting a patient's stem cells, engineering them to produce a form of hemoglobin, and infusing them back into patients.

"If the bellwether can't launch a product that they've been spending billions of dollars on over the course of 10 years, how is a $400 million company somewhere going to do it?" Faroohar told BioPharma Dive.

Bluebird isn't the only gene therapy leader to get knocked recently.

Swiss pharma giant Novartis remains on damage control following a data scandal that, to some extent, tarnished the approval of its Zolgensma gene therapy. Roche's acquisition of Spark Therapeutics, meanwhile, is taking longer than expected because of antitrust concerns.

Delays to the Spark deal may be having a particularly outsized effect on gene therapy stocks. Signs that the Federal Trade Commission took issue with the pairing, which many analysts assumed would be a sort of "check-the-boxes" acquisition, started to show up in early April.

No gene therapy acquisitions have been announced since, and Faroohar doesn't expect that to change until buyers have more clarity on what's holding up Roche. With the deal's timeline already extended by months, shareholders of other companies might not be willing to wait around for a resolution.

"If you paralyze the acquirers, that makes it very difficult to make a compelling case for a lot of these companies that certainly wouldn't be able to commercialize their own products without raising a lot of diluted capital," Faroohar said.

Van Buren sees the Spark deal as a more minor issue, given that gene therapy continues to be one of the hottest areas in drug development. Even so, he acknowledged that it could discourage "natural bidders" from coming to the table, which lowers the probability of certain acquisitions.

The gene therapy field evolved rapidly over the last decade and, by 2025, the Food and Drug Administration expects to clear for market 10 to 20 cell or gene therapy products annually.

Investor sentiment is shifting with the times. As Bluebird, Novartis and Spark Therapeutics proved these treatments can move through the clinic and gain regulatory approval, investors became increasingly interested in marketing and manufacturing strategies even for drugs in early development.

"For so long, [gene therapy companies] didn't really trade on, 'What's my margin structure going to be? What's my distribution method? How do I realize attractive pricing in Europe versus Japan versus the U.S.?'" Faroohar said.

Now, investor awareness "about some of these very nuanced commercial questions is catching up."

One of their biggest commercial concerns revolves around insurance coverage, since the U.S. insurance system wasn't designed to handle incredibly expensive, potentially one-time treatments like Zolgensma, which Novartis offers at $2.1 million through a five-year installment plan.

Another commercial sticking point has been manufacturing. Bluebird, for example, pinned Zynteglo's slower launch on tweaks the company was making to the therapy's production process.

Ensuring consistent and quality manufacturing will likely be a challenge for others too. PwC proposes in a new report that the growing interest in gene therapy will lead to greater competition for the time and resources of contract manufacturers working in the space. The competition could, in turn, result in higher costs or supply constraints, and may force companies to invest more in their own manufacturing a development seen with projects begun by Novartis, Pfizer, Sarepta and Bluebird.

"The days of 100% outsourcing and letting somebody else deal with it I don't see that being the standard model," said Karen Young, U.S. Pharmaceutical and Life Sciences Leader at PwC.

The industry, however, is still getting acclimated to the small-scale, highly personalized, logistically daunting processes required for cell and gene therapy production. Building in-house capabilities and a team with the technical know-how to run them would likely be an expensive, time-consuming endeavor.

These challenges are, of course, predicated on a gene therapy having positive clinical data. On that measure, analysts have observed investors becoming harder to impress.

Van Buren noted to BioPharma Dive how shares of Adverum Technologies, which is working on gene therapies for eye and rare diseases, plummeted in mid-September because investor expectations about one of the company's trial readouts were "almost impossibly high."

"It got crushed as if a trial failed, when it was actually an objectively positive outcome," he said.

Adverum's therapy targets an eye disease known as wet AMD, which already has treatment options in Regeneron's Eylea and Roche's Lucentis. Both Van Buren and Faroohar expect that in markets where patients respond well to the standards of care, such as wet AMD and hemophilia, there will be even more pressure for gene therapy developers to show their treatments are safe and long-lasting.

Data and post-approval obstacles, combined with potentially diminished M&A prospects, set the stage for a tough road ahead for gene therapy stocks.

"It becomes harder to put together a compelling long-case for a lot of gene therapy stocks, even if they continue to produce a very attractive set of data and potentially transformative clinical products," Faroohar said.

Editor's Note:Paper losses for the group of gene therapy companies included in BioPharma Dive's analysis were calculated by using historical valuations compiled by Koyfin, measured against current market capitalizations. Stock change over 52 weeks was measured from Oct. 1, 2018 to Oct. 1, 2019.

Publicly traded biotechs were included based on whether gene therapy, or gene editing, made up the bulk of their pipeline, yielding a list that's representative of the field but not exhaustive. Large pharmas involved in gene therapy were not included, nor were companies dedicated to autologous or allogeneic cancer cell therapies.

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NIH researchers create new viral vector for improved gene therapy in sickle cell disease – National Institutes of Health

Posted: October 4, 2019 at 7:47 am

News Release

Wednesday, October 2, 2019

Forward-oriented design might boost treatment effectiveness and broaden use.

Researchers at the National Institutes of Health have developed a new and improved viral vectora virus-based vehicle that delivers therapeutic genesfor use in gene therapy for sickle cell disease. In advanced lab tests using animal models, the new vector was up to 10 times more efficient at incorporating corrective genes into bone marrow stem cells than the conventional vectors currently used, and it had a carrying capacity of up to six times higher, the researchers report.

The development of the vector could make gene therapy for sickle cell disease much more effective and pave the way for wider use of it as a curative approach for the painful, life-threatening blood disorder. Sickle cell disease affects about 100,000 people in the United States and millions worldwide.

Our new vector is an important breakthrough in the field of gene therapy for sickle cell disease, said study senior author John Tisdale, M.D., chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung, and Blood Institute (NHLBI). Its the new kid on the block and represents a substantial improvement in our ability to produce high capacity, high efficiency vectors for treating this devastating disorder.

Researchers have used virus-based vehicles for years in gene therapy experiments, where they have been very effective at delivering therapeutic genes to bone marrow stem cells in the lab before returning them to the body. But theres always room for improvement in their design in order to optimize effectiveness, Tisdale noted. He compared the new virus-based vehicle to a new and improved car that is also far easier and cheaper for the factory to produce.

The study was supported by the NHLBI and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), both part of the NIH. It was published online today in Nature Communications.

Sickle cell disease is an inherited blood disorder caused by a mutation, or misspelling, in the beta-globin gene (or -globin gene). This mutation causes hemoglobin, the main ingredient of blood cells, to produce sickle-shaped cells that can stick to the walls of blood vessels, causing blockage, pain, anemia, organ damage, and early death. With gene therapy, doctors modify the patients bone marrow hematopoietic (blood-producing) stem cells in the lab by adding a normal copy of the beta-globin gene through the use of a viral vector. They then reinfuse the modified stem cells into the patient to produce normal, disc-shaped red blood cells.

For the past 30 years, researchers have been designing these beta-globin vectors in a reverse structural orientation, meaning the therapeutic genes incorporated into the virus are translated, or read, from right to left by the viral vector-making machinery much like reading an English sentence backwards. The reason for the reverse orientation is the sensitive expression of a key molecular component of the vector called intron 2. This segment is required for high-level beta-globin gene expression but gets clipped out during the normal vector preparation process if it is left in the natural, forward direction. Gene therapy trials using reverse-oriented vectors for sickle cell disease and beta-thalassemia have largely been encouraging, the researchers said, but this complicated gene translation process has made vector preparation and gene-transfer efficiency more difficult.

About 10 years ago, Tisdale and Naoya Uchida, M.D., Ph.D., a staff scientist in his lab, searched for an improved delivery vehicle like designing a better car and decided to undertake a radical redesign of the beta-globin vector. They came up with a unique work-around design that left intron 2 intact and created the new forward-oriented beta-globin vector. In contrast to the old vector, the gene sequence, or message, of the new beta-globin vector is read from left to right like reading a normal sentence making the gene translation approach less complicated, Tisdale explained.

The researchers tested the new vectors in mice and monkeys and compared the results to reverse-oriented vectors. They found that the new vectors could transfer a much higher viral load up to six times more therapeutic beta-globin genes than the conventional vectors and had four to 10 times higher transduction efficiency, a measure of the ability to incorporate corrective genes into repopulating bone marrow cells. The new vectors also showed a capacity for longevity, remaining in place four years after transplantation. Researchers also found that they could be produced in much higher amounts than the conventional vectors, potentially saving time and lowering costs associated with large-scale vector production.

Our lab has been working on improving beta-globin vectors for almost a decadeand finally decided to try something radically differentand it worked, Tisdale said. These findings bring us closer to a curative gene therapy approach for hemoglobin disorders.

The new vector, for which the NIH holds the patent, still needs to undergo clinical testing in humans. Already an estimated 27 people with sickle cell disease have undergone experimental gene therapy using conventional vectors. Through its Cure Sickle Cell Initiative, NIH is working to accelerate the development of these and other new genetic therapies, including gene editing, with the goal of finding a cure for the disease. The initiative is part of NIHs larger multi-pronged approach to reducing the burden of blood disorders. People with sickle cell disease can visit clinicaltrials.gov to find a clinical trial that is actively enrolling.

About the National Heart, Lung, and Blood Institute (NHLBI):NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visitwww.nhlbi.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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NIH researchers create new viral vector for improved gene therapy in sickle cell disease - National Institutes of Health

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New Method Produces High Quantities of Viral Vectors for Gene Therapy – SMA News Today

Posted: October 4, 2019 at 7:47 am

Scientists have developed a fast, efficient and economical method to create viral delivery vectors used in gene therapy to deliver modified versions of genes to treat disorders caused by genetic defects, including spinal muscular atrophy (SMA).

The findings were reported in the study, Production of adeno-associated virus vectors for in vitro and in vivo applications, and published in Scientific Reports.

Gene therapy is a relatively new approach that has been gaining popularity in clinical practice as a way to treat diseases caused by genetic mutations. It involves delivering a functional version of a gene to correct or replace a faulty gene within specific cells in the body.

In order to deliver the corrected version of the gene to cells, researchers use special viral vectors that work as carriers. Adeno-associated viruses, or AAVs, are one of the most used viral vectors in gene therapy due to their ability to infect and deliver the corrected gene to both dividing and non-dividing cells, without causing any harm to patients.

Gene therapy already is being used as a form of SMA treatment. The recent approval of Zolgensma (AVXS-101), a gene therapy co-developed by AveXis and Novartis, for the treatment of all types of SMA in newborns and toddlers up to the age of 2, was a historical landmark that highlighted the potential of AAV-based gene therapies to treat rare genetic disorders.

Most protocols recommend AAV purification from producer cells, grown in large cell stacks or cell culture factories to obtain sufficient AAVs for animal experiments. However, producer cells also release large quantities of AAV into the culture medium, which often remains unused, the investigators said.

In this study, researchers from the Boston University School of Medicine (BUSM) described a new protocol that allows them to maximize the quantity of AAVs that can be purified from producer cells and their culture medium in a fast, efficient and economic way.

With the new protocol, which involved several separation and purification laboratory techniques, they managed to obtain up to one milliliter of AAVs at a concentration of 10101011 viral genome copies per microliter, using five times less the number of producer cells normally used in conventional protocols.

They also showed the AAVs produced with the new protocol were viable and retained their ability to efficiently infect and deliver modified genes to cells in vitro and in vivo (outside and inside an organism, respectively).

Our protocol helps to produce AAVs efficiently and economically in regular laboratories so that researchers can easily conduct pre-clinical trialsforgene therapy, Markus Bachschmid, PhD, assistant professor of medicine at BUSM and corresponding author of the study, said in a press release.

Several labs in the Boston area and Japan have already tested this new protocol and found it useful, said Reiko Matsui, MD, assistant professor of medicine at BUSM and co-corresponding author of the study. Our hope is that many laboratories can adapt these procedures to accelerate research and promote gene therapy.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells cells that make up the lining of blood vessels found in the umbilical cord of newborns.

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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