An intriguingbut far from provenHIV cure in the ‘So Paulo Patient’ – Science Magazine

HIV, shown here budding from cell, remains stubbornly resistant to cure strategies because its DNA can lie silently in host chromosomes for years.

By Jon CohenJul. 7, 2020 , 9:00 AM

A 36-year-old man in Brazil has seemingly cleared an HIV infectionmaking him the proof of principle in humans of a novel drug strategy designed to flush the AIDS virus out of all of its reservoirs in the body. After receiving an especially aggressive combination of antiretroviral (ARV) drugs and nicotinamide (vitamin B3), the man, who asks to be referred to as the So Paulo Patient to protect his privacy, went off all HIV treatment in March 2019 and has not had the virus return to his blood.

The patients story is remarkable, says Steven Deeks, an HIV/AIDS clinician at the University of California, San Franciscowho was not involved with this study. But he and others, including the study leaders, caution that the success hasnt been long or definitive enough to label it a cure. Interesting anecdotes have long driven the HIV cure field, and they should be considered largely as hypothesis-generating observations that can simulate new areas of investigation, says Deeks, who also conducts HIV cure research.

Most people who suppress HIV with ARVs and later stop treatment see it come racing back to high levels within weeks. Not only did the So Paulo Patient not experience a rebound, but his HIV antibodies also dropped to extremely low levels, hinting at the possibility he may have cleared infected cells in the lymph nodes and gut.

Ricardo Diaz of the Federal University of So Paulo, the clinical investigator running the study, says he doesnt know whether the patient is cured. He has very little antigen, Diaz says, referring to HIV proteins that trigger the production of antibodies and other immune responses. But he notes his team has not sampled the mans lymph nodes or gut for the virus since he stopped treatment. Diaz discussed the patient today at a press conference for AIDS 2020, the 23rd International AIDS Conference taking place virtually this week, and he plans to present the study in full tomorrow.

Only two people are known to have been cured of their HIV infections:Timothy Ray Brown and a man who has asked to be referred to as the London Patient; both received bone marrow transplants as part of a treatment for cancers. The transplants cleared their infections and gave them new immune systems that resist infection with the virus. But bone marrow transplants are expensive, complicated interventions that can have serious side effects, making them an impractical cure for the 38 million people now living with the AIDS virus.

Other potential HIV cure cases have received intense media attention only to see the virus return after prolonged absences. Most soberingly, a baby in Mississippi who started ARVs shortly after birth stopped treatment at 18 months and was thought to be cured until the virus suddenly resurfaced more than 2 years later. Several adults who had bone marrow transplants and appeared to have been cured were not.

HIV has proven particularly difficult to eliminate because the virus weaves its genetic material into human chromosomes, where it can lie dormant, escaping the immune surveillance that typically eliminates foreign invaders. These silently infected cells may persist, perhaps indefinitely, because they have stem cell-like properties and can make clones of themselves. Researchers have come up with several strategies to flush reservoirs of cells that harbor latent HIV infections, but none have provedeffective.

To compare different reservoir-clearing strategies, Diaz and colleagues in 2015 recruited the So Paulo Patient and other individuals who had controlled their HIV infections with ARVs. The most aggressive approach, used in this man and four others, added two ARVs to the three they were already taking, in the hopethis would rout out any HIV that might have dodged the standard treatment. On top of this intensification, the study group received nicotinamide, which can, in theory, prod infected cells to wake up the latent virus. When those cells make new HIV, they either self-destruct or are vulnerable to immune attack.

After 48 weeks on this intensified schedule, the five trial participants returned to their regular three-drug regimen for 3 years, after which they stopped all treatment. Four saw the virus quickly return, but the So Paulo Patient has now gone 66 weeks without signs of being infected. Sensitive tests that detect viral genetic material did not find HIV in his blood. An even more sensitive test, which mixed his blood with cells that are susceptible to HIV infection, produced no newly infected cells.

Intriguingly, during the intensification period with nicotinamide, this man was the only one of the five who twice had the virus detected on standard blood tests. To Diaz, this suggests that latently infected cells had been roused, leading to blips of viral production. Im always trying to be a little bit the devils advocate, but in this case, Im optimistic, Diaz says. Maybe this strategy is not good for everybody because it only worked in one out of five here. But maybe it did get rid of virus. I dont know. I think this is a possibility.

Deeks says he does not know of any report, other than the two people cured by bone marrow transplants, of decreases in HIV antibody levels after stopping treatment. One large, outstanding question, he says, is whether the man indeed stopped taking his ARVs. I have not taken any HIV medication since March 30, 2019, the So Paulo Patient says. Diaz plans to confirm this by examining the mans blood for ARVs.

Another unknown is how soon the man started ARVs after becoming infected with HIV. Studies have shown that a small percentage of people who begin ARV treatment shortly after becoming infected have a better chance of controlling the virus for prolonged periods if they cease the drugs, presumably because they never built large reservoirs of infected cells. The So Paulo Patient started treatment 2 months after being diagnosed in October 2012. As with most people who become infected with HIV, he cannot say for certain when transmission occurred, but he suspects it was in June 2012. The only certainty is that he tested negative in 2010.

Its also unclear how nicotinamide would awaken silent infected cells. HIV DNA remains latent when it tightly spools around chromosome proteins known as histones. To make viral copies, it must unspool, and Diaz points to evidence that nicotinamide can trigger this unspooling in different ways.

Sharon Lewin, an HIV cure researcher who directs the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, finds the antibody response intriguing. But she underscores it is not a convincing, controlled experiment. We need to move beyond case reports of HIV remission, Lewin says. I would be super excited to see long term remission in multiple participants in a clinical trial. This is what the field needs to really advance.

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An intriguingbut far from provenHIV cure in the 'So Paulo Patient' - Science Magazine

Business impacts of COVID-19 on Regenerative Medicine Market. Strategies of Major Industry Competitors – Cole of Duty

The increasing incidence of genetic disorders and chronic diseases is one of the biggest factors responsible for the burgeoning sales of regenerative medicine throughout the globe. The rising adoption of sedentary lifestyles and unhealthy dietary habits of the people all around the world are the main reasons causing the high prevalence of chronic diseases across the world. According to the World Health Organization (WHO), almost 17.9 million deaths are recorded every year because of cardiovascular diseases. Moreover, the cardiovascular diseases account for nearly 31% of the total deaths occurring across the world every year.

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The other major factors propelling the demand for regenerative medicine are the soaring investments being made by the governments of many countries in research and development activities in the domain of regenerative medicine, surging number of regenerative medicine companies throughout the world, and rapid technological developments in tissue engineering areas and stem cell research. Due to these factors, the global regenerative medicine market is expected to exhibit huge expansion over the coming years.

Across the globe, the regenerative medicine market is predicted to record the fastest growth in the Asia-Pacific (APAC) region in the upcoming years. This is mainly credited to the improving healthcare facilities and infrastructure in the region and the subsequent rise in stem cell research in the developing nations of APAC. For instance, the Chinese government has recently approved R&D activities pertaining to the human embryonic stem cells, which has in turn, encouraged more research on the clinical potential of the stem cells in the country.

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Researchers uncover a critical early step of the visual process – Newswise

Newswise The key components of electrical connections between light receptors in the eye and the impact of these connections on the early steps of visual signal processing have been identified for the first time, according to research published today in Science Advances by The University of Texas Health Science Center at Houston (UTHealth).

To understand fully how the light receptors, called photoreceptors, impact the early stages of the process of vision, researchers have traditionally focused their attention on how two key sensory cells rods and cones convert elementary particles of light into electrical signals and how these signals are relayed to the brain through devoted circuits. Rods are used for night vision and cones are used for daytime and color vision. While it has been known for some time that electrical signals can spread between photoreceptors through cell connectors called gap junctions, the nature and function have remained poorly understood.

This research will lead to a better understanding of how the retina processes signals from the rods and the cones in the eyes, in particular under ambient lighting conditions when both photoreceptor types are active, such as at dawn and dusk. This knowledge is currently missing and may have to be taken into consideration when designing photoreceptor or retinal implants to restore vision, said Christophe P. Ribelayga, PhD, co-lead author of the study and associate professor and Bernice Weingarten Chair in the Ruiz Department of Ophthalmology & Visual Science at McGovern Medical School at UTHealth.

Co-lead author Steve Massey, PhD, is professor, Elizabeth Morford Chair, and research director in the Ruiz Department of Ophthalmology & Visual Science at McGovern Medical School at UTHealth.

The coupling or communication between rods and cones in the retina is critical for understanding how the visual signaling process works.

What the researchers discovered, to their surprise, is that rods do not directly communicate with other rods and cones seldom communicate directly with other cones. Instead, the majority of signaling happens through communication between rods and cones. Researchers identified a specific protein called connexin36 (Cx36) as the main component of rod/cone gap junctions.

We noted that every single rod has electrical access to a cone and that cone/cone gap junctions are very rare, Massey said. We estimated that more than 95% of all gap junctions between photoreceptors are rod/cone gap junctions; they have the largest volume and the largest conductance. So, rod/cone gap junctions dominate the network of photoreceptors both in size and number.

To help researchers better understand how the photoreceptor network is organized, they developed genetic mouse strains for the work that were bred to eliminate gap junctions in either rods or cones.

Our study has important implications, said Ribelayga. Our data position rod/cone gap junctions as the keystone of the photoreceptor network. The rod/cone gap junction is the entry of a rod pathway through which signals of rod origin can travel across the retina. We have thus generated mice that are essentially deficient for the entry of this pathway. In future experiments, we will use these animals to determine the functional importance of the rod/cone pathway in the retinal processing of rod signals and for vision.

In 2018, researchers in the Ruiz Department of Ophthalmology & Visual Science received more than $4 million in grants from the National Institutes of Healths National Eye Institute to study photoreceptor development, function, and electrical interactions. Ribelayga and Massey led the effort to lay out the architecture of the network of electrically coupled receptors, a critical step toward a better understanding of how photoreceptors encode light signals and how the retina processes these signals.

Additional UTHealth authors include Nange Jin, PhD; Zhijing Zhang, PhD; Joyce Keung, PhD; Munenori Ishibashi, PhD; Lian-Ming Tian; Iris Fahrenfort, PhD; Takae Kiyama, PhD; Chai-An Mao, PhD; David W. Marshak, PhD; Jiaqian Wu, PhD; Haichao Wei, PhD; and Yanan You, PhD. Marshak is with McGovern Medical Schools Department of Neurobiology and Anatomy; and Wu, Wei, and You are with the UTHealth Center for Stem Cell and Regenerative Medicine at the Brown Foundation Institute of Molecular Medicine.

Other authors include Sean B. Youn with Rice University; Eduardo Solessio, PhD; and Yumiko Umino, PhD, with the Center for Vision Research and SUNY Eye Institute at SUNY Upstate Medical University; and Friso Postma, PhD; and David L. Paul, PhD, with Harvard University.

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Researchers uncover a critical early step of the visual process - Newswise

Oncologie Expands and Strengthens Management Team with Key Appointments and Promotions – BioSpace

WALTHAM, Mass., July 09, 2020 (GLOBE NEWSWIRE) -- Oncologie, Inc., a precision medicine company using an innovative RNA-based biomarker platform to develop novel, targeted oncology therapies, today announced an expansion of its management team with the appointments of Matthew Osborne as Chief Financial Officer, Hagop Youssoufian, M.D., as Interim Chief Medical Officer, Bill McDonald, Ph.D., as Vice President of Chemistry, Manufacturing and Controls (CMC), as well as the promotion of Kerry Culm-Merdek, Ph.D., to Vice President of Clinical Development.

We are pleased to expand Oncologies management team with the additions of Matt, Hagop and Bill, and the promotion of Kerry, and look forward to their contributions, said Laura Benjamin, Ph.D., Founder and CEO of Oncologie. Their collective experience and leadership will be critical as we further develop and deploy our RNA-based biomarker platform to advance the state of the art of precision medicine to identify the right patients for our clinical stage programs, Navicixizumab and Bavituximab.

Mr. Osborne brings to Oncologie more than 20 years of leadership, financial and industry experience, gleaned from years on Wall Street and through professional roles with small to large cap biotechnology companies. In these roles, he successfully led multiple equity financings, applying his expertise across disciplines spanning scientific, financial, strategic planning, investor relations and corporate communications functions. Before joining the company in 2020, Mr. Osborne served as Chief Financial Officer at Unum Therapeutics, Inc. Prior to joining Unum Therapeutics, Mr. Osborne served as Head of Corporate Affairs, Communications and Investor Relations at Voyager Therapeutics, Inc., and through similar roles at Shire, Plc (acquired by Takeda Pharmaceutical Company in 2019), Synageva BioPharma Corp. (acquired by Alexion Pharmaceuticals, Inc. in 2015) and Vertex Pharmaceuticals Incorporated. Mr. Osbornes Wall Street experience includes serving as a sell-side analyst at Lazard Capital Markets and Leerink Swann (now SVB Leerink), where he covered small to large cap biotechnology companies, analyzed drug launches and launched several initial public offerings. He received a B.S. in Biology from Syracuse University and an M.B.A. from the DAmore-McKim School of Business at Northeastern University.

Dr. Youssoufian is a physician-scientist with more than 25 years of experience in drug development working with seed-stage ventures to multi-national biotech and pharmaceutical corporations. After a successful academic career as a clinician, teacher and NIH-funded investigator, he held increasingly senior roles in clinical and translational science including Head of Experimental Medicine at Bristol-Myers Squibb Company, Distinguished Scientist at Sanofi Aventis, Chief Medical Officer at ImClone Systems Incorporated, President of Research and Development and Chief Medical Officer at Ziopharm Oncology, Inc., Executive Vice President of Research and Development at Progenics Pharmaceuticals, Inc., and Chief Medical Officer at BIND Therapeutics, Inc. He supported or led the development and approval of a number of medicines including Sprycel, Taxotere, Erbitux, Cyramza, Lartruvo and Copiktra. He is an elected member of the American Society for Clinical Investigation, the recipient of many national and international awards, and the author of more than 100 publications. He received a B.S. in biology from Boston College and M.Sc./M.D. from University of Massachusetts Medical School, followed by fellowships at Johns Hopkins University, Harvard University and the Massachusetts Institute of Technology.

William Bill McDonald, Ph.D., brings more than 20 years of experience in process development and the manufacturing of antibodies, recombinant enzymes, antigens, antibody targets, viral vectors and vaccines. Prior to joining Oncologie, Bill served as Vice President, CMC at Contrafect Corporation where he was responsible for all CMC activities for Contrafects novel biologics platform of anti-microbial therapies. Previously, Bill served as Executive Director and Manufacturing Site Head at Celldex Therapeutics, Inc., where he oversaw the Fall River GMP manufacturing facility and was responsible for internal manufacturing of all early clinical stage biologics. Bill also held roles of increasing responsibility at Synageva BioPharma Corp. (acquired by Alexion Pharmaceuticals, Inc. in 2015), including Senior Director of Process Development. He also previously served as Head of Process Science at Pfizer, Inc., Director of Antigen Production at Genocea Biosciences Inc. and Director of Biochemistry at VaxInnate Corporation. Within the scope of technical operations, he has supported the development and manufacture of several approved biologics including Kanuma, Soliris and Strensiq. Bill received a B.S. in Microbiology from the University of Florida and received a Ph.D. in Molecular Biology at Cornell University.

Kerry Culm-Merdek, Ph.D., brings over 15 years of clinical drug development expertise and experience in small molecule and therapeutic protein development in rare disease and oncology indications including her role as Head of Clinical Pharmacology and Quantitative Bioanalytics at ImmunoGen Inc., where she was responsible for clinical pharmacology strategy for global clinical and preclinical development of oncology therapies. Prior to joining ImmunoGen, Kerry spent 13 years at Sanofi Genzyme, most recently serving as a Global Project Head, where she led the therapy project teams for Fabry disease, Gaucher disease type 3 and multiple gangliosidosis/galatosialidosis indications. Kerry received a B.S. in Biochemical Pharmacology from the State University of New York at Buffalo. She received a Ph.D. in Pharmacology and Experimental Therapeutics at Tufts University School of Medicine.

About Bavituximab

Bavituximab is an investigational chimeric monoclonal antibody that targets the activity of phosphatidylserine (PS). Bavituximab is believed to reverse PS-mediated immunosuppression by blocking the engagement of PS with its receptors, as well as by sending an alternate immune activating signal. PS-targeting antibodies have been shown to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. This mechanism may play an important role in allowing other cancer therapies to more effectively attack tumors by reversing the immunosuppression that limits the impact of those treatments. Oncologie is conducting a Phase 2 trial of bavituximab plus pembrolizumab as a second-line treatment in patients with advanced gastric or gastroesophageal cancer. Using its biomarker platform, Oncologie is analyzing patient tissue samples from this on-going trial with results expected later this year to inform future clinical development for this program.

About Navicixizumab

Navicixizumab is an anti-DLL4/VEGF bispecific antibody designed to inhibit both Delta-like ligand 4 (DLL4) in the Notch cancer stem cell pathway as well as vascular endothelial growth factor (VEGF) and thereby induce potent anti-tumor responses while mitigating certain angiogenic-related toxicities. In preclinical studies, navicixizumab demonstrated robust in vivo anti-tumor activity across a range of solid tumor xenografts, including colon, ovarian, lung and pancreatic cancers, among others. In a Phase 1a trial of 66 patients with various types of refractory solid tumors, treatment with single agent navicixizumab generated an overall response in three of 12 (25%) patients with ovarian cancer. In a Phase 1b trial in platinum-resistant ovarian cancer patients who had failed more than two prior therapies including bevacizumab, treatment with navicixizumab plus paclitaxel generated an interim overall response in 10 of 30 (33%) patients. Treatment-related adverse events in the Phase 1b trial were manageable and included hypertension (58%), headache (29%), fatigue (26%) and pulmonary hypertension (18%). Using its RNA-based biomarker platform, Oncologie is analyzing patient tissue samples from all navicixizumab trials with results expected later this year to inform future clinical development with this program. The FDA granted Fast Track designation to navicixizumab for the treatment of high-grade ovarian, primary peritoneal or fallopian tube cancer in patients who have received at least three prior therapies and/or prior treatment with bevacizumab.

About Oncologies RNA-based Biomarker Platform

Predictive biomarkers historically worked on single-driver mutations yet only approximately 10% of cancer patients have known driver mutations with available targeted therapies. Using its proprietary biomarker platform, Oncologie is advancing a new paradigm of precision oncology with an RNA-based approach to identify the dominant biology in the tumor microenvironment. This could improve clinical outcomes by matching patients to therapies with a mechanism of action that targets that specific biology and expand precision medicine to those therapies whose potential remains unrealized. Oncologie is further optimizing the biomarker platforms tumor microenvironment panel through multiple research collaborations, including a collaboration with Moffitt Cancer Center.

About Oncologie, Inc.

Oncologie, Inc. aims to advance the state of the art of precision medicine to dramatically improve the lives of people with cancer. Leveraging a deep understanding of the evolving biology of cancer, Oncologie is developing unique RNA-based biomarker panels to match patients to novel, targeted therapies that modulate the bodys tumor immune system and angiogenesis pathways. Oncologie, Inc., based in Waltham, Massachusetts, and Oncologie Shanghai Co., Ltd., based in Shanghai, China, are subsidiaries of Oncologie, Ltd., and are working with global partners to acquire and further develop innovative drugs for cancer patients around the world. For more information on Oncologie, Inc., please visit https://oncologie.com/.

Investor and Media Contact:

Ashley R. Robinson LifeSci Partners, LLC arr@lifesciadvisors.com

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Oncologie Expands and Strengthens Management Team with Key Appointments and Promotions - BioSpace