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COVID & Genetics - CCR5 Leronlimab therapy checked COVID-19 inflammation
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DNA Could Hold Clues to Varying Severity of COVID-19
https://www.the-scientist.com/news-opinion/dna-could-hold-clues-to-varying-severity-of-covid-19-67435
What about Maravioc or Fuzeon
Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19
https://www.medrxiv.org/content/10.1101/2020.05.02.20084673v1
CCR5 Receptor Appears Effective in Modulating Inflammation.
Leronlimab therapy checked COVID-19 inflammation
This manuscript, Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19, has been shared with the World Health Organization and is currently under peer review, said CytoDyn, Inc., as of May 6, 2020.
As described in the pre-print, in a cohort of 10 critically ill patients, after treatment with leronlimab, these critically ill patients experienced reversed hyperimmune activation and inflammation, as well as reversed immunosuppression, thereby facilitating a more effective immune response correlated with decreases in SARS-CoV-2 level in blood.
These results demonstrate a novel approach to resolving unchecked inflammation while restoring immunologic deficiencies.
https://www.precisionvaccinations.com/leronlimab-therapy-checked-covid-19-inflammation
The first patient with breast cancer has been treated with leronlimab in a phase II basket trial for 22 solid tumors, according to another update from CytoDyn. The study aims to evaluate leronlimab in approximately 22 solid tumors, such as melanoma, glioblastoma, throat, lung, stomach, colorectal, breast, testicular, ovarian, uterine, pancreatic, and bladder cancers, among others.2
Investigators plan to enroll 30 patients with CCR5-positive locally advanced or metastatic solid tumors. Patients will receive a subcutaneous dose of leronlimab at 350 mg. The trial is being conducted at several institutions across the United States. Preliminary data are expected within 3 to 4 weeks of the initial injection for each patient. The primary end point is progression-free survival.
Treatment with CytoDyn's Leronlimab Indicates Significant Trend Toward Immunological Restoration in Severely Ill COVID-19 Patients.....a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that the three-day effect of leronlimab in eight severely ill COVID-19 patients demonstrated a significant improvement in several important immunologic bio-markers. Patient test data reveals improvement in cytokines, IL-6, and a trend toward the normalization of the CD4/CD8 ratio.
https://www.cytodyn.com/newsroom/press-releases/detail/405/treatment-with-cytodyns-leronlimab-indicates-significant
In the cancer setting, CCR5 plays a potential role in tumor invasion, metastases, and tumor microenvironment control. Increased expression of CCR5 may indicate disease status in several cancers, and several published studies have indicated that blocking CCR5 may reduce tumor metastases in laboratory and animal models of aggressive breast cancer and prostate cancer.
"We are very excited to start our Phase2b/3 trial in patients with severe COVID-19. Based on the promising results from the EIND patients, we are hopeful that this randomized, placebo-controlled trial will give us the data needed for FDA approval and ultimately the basis to use leronlimab to save lives in this pandemic," Bruce Patterson, MD, chief executive officer, founder, IncellDx, and advisor to CytoDyn, said in a statement. The company also announced that about 30 patients have received leronlimab under the Emergency Investigational New Drug authorizations granted by the FDA. The company also announced that about 30 patients have received leronlimab under the Emergency Investigational New Drug authorizations granted by the FDA. The FDA granted clearance forthe initiation and enrollment of the clinical trial for severe and critically ill patients with COVID-19. Investigators aim to enroll 390 patients, who will be randomized 2:1 to receive either leronlimab or placebo. Leronlimab, a CCR5 antagonist, will be administered for 2 weeks in this trial. The primary end point of the study is the mortality rate at 28 days, and a secondary end point is the mortality rate at 14 days. An interim analysis will be performed on the first 50 patients. This agent has been granted a Fast Track designation from the FDA for 2 potential indications of COVID-19. Overall, leronlimab has been evaluated in 9 clinical trials in more than 800 patients and has met its primary end points in a pivotal phase III trial of patients with HIV-infected patients in combination with standard antiretroviral therapies.
The first patient with breast cancer has been treated with leronlimab in a phase II basket trial for 22 solid tumors, according to another update from CytoDyn. The study aims to evaluate leronlimab in approximately 22 solid tumors, such as melanoma, glioblastoma, throat, lung, stomach, colorectal, breast, testicular, ovarian, uterine, pancreatic, and bladder cancers, among others.2
Investigators plan to enroll 30 patients with CCR5-positive locally advanced or metastatic solid tumors. Patients will receive a subcutaneous dose of leronlimab at 350 mg. The trial is being conducted at several institutions across the United States. Preliminary data are expected within 3 to 4 weeks of the initial injection for each patient. The primary end point is progression-free survival..
.....https://www.targetedonc.com/view/first-patient-treated-in-phase-iibiii-trial-of-leronlimab-for-covid19
DNA Could Hold Clues to Varying Severity of COVID-19
https://www.the-scientist.com/news-opinion/dna-could-hold-clues-to-varying-severity-of-covid-19-67435
Among the many mysteries that remain about COVID-19, the disease caused by the new coronavirus, is why it hits some people harder than others. Millions of people have been infected, but many never get sick. Those who do can experience an ever-expanding array of symptoms, including loss of smell or taste, pink eye, digestive issues, fever, cough, and difficulty breathing. Although the elderly, those with pre-existing conditions such as heart disease, and men are most likely to suffer severe complications, hundreds of young and previously healthy people have died from the disease in the US alone.
In recent weeks, researchers have begun asking whether genetics could influence the severity of symptoms.
So far, they know "basically nothing," Wendy Chung, a clinical geneticist and physician at Columbia University, tells The Scientist. She is one of hundreds of scientists launching studies to interrogate the human genome for answers. Chung and her team are racing to "recycle" and bank nasal swabs and other clinical samples from COVID-19 patients across the New York-Presbyterian Hospital System, currently in the epicenter of the coronavirus pandemic.
The researchers plan to extract the patients' DNA and scan the genomes for tiny sequence variations associated with symptoms listed in their electronic health records.
Prior research has uncovered gene variants that can alter a person's chances of contracting an infectious disease. The most famous example is a mutation in the CCR5 gene, which offers protection against HIV.
Other variants can affect what happens once the virus is inside the human body, leading to strikingly disparate outcomes from one person to the next, says Priya Duggal, a geneticist at Johns Hopkins University. Duggal has previously shown that variants in the human leukocyte antigen (HLA) genes, which influence the body's immune response, may explain why some people spontaneously clear hepatitis C infection whereas others are left with chronic disease.
Duggal says understanding how genetic background affects people's responses to infection may give scientists proteins or pathways to target to boost the immune response with a vaccine. That's the reason she recently expanded her lab's research from HIV, hepatitis, and other pathogens to look at the SARS-CoV-2 coronavirus. She is planning a study of younger people who have been hospitalized after contracting the virus to see if there is a genetic basis for their more serious disease, though she hesitates to guess what might come up in her search.
"I think we're so bad at predicting [which genes matter]. We've been terrible in the past and I think a lot of it is because we don't fully understand everything that's going on in the immune system," she says. One of the reasons COVID-19 can be so fatal to some people is because of their bodies elicit an overzealous immune response called a cytokine storm, which may originate in their DNA. A small study of patients who died from the 2009 H1N1 flu outbreak found that many carried mutations that triggered this self-destructive flood of cytokine molecules.
Results from studies on the genetics of COVID-19 susceptibility and severity are beginning to trickle in. One study suggests that variants in the HLA genes likely play a role. Others point to differences in the ABO blood type, as well as variants in the ACE2 gene, which codes for the protein SARS-CoV-2 latches onto to infect human cells. But the findings are all preliminary, and require follow-up with larger datasets.
See "Why Some COVID-19 Cases Are Worse than Others"
Andrea Ganna, a biostatistician at the University of Helsinki, is leading a major effort to pool data from genomics projects around the globe. The COVID-19 Host Genetics Initiative includes 117 studies on its website, and more than 439 scientists on its Slack channel. Ganna says several big biobanks have agreed to share the DNA data they have been gathering since before the pandemic, including the Penn Medicine Biobank, which has 60,000 participants; FinnGen, which has collected DNA from 5 percent of Finland's entire population; and the UK Biobank, one of the world's largest with samples from 500,000 volunteers.
"I'm quite confident when these big players come on board, we can grow our databases exponentially in the next month and that we will find something," says Ganna, who is hoping to identify gene variants associated with COVID-19 outcomes.
Earlier this month, the personal genomics company 23andMe announced it would be tapping its database of more than 10 million customers for clues. Joyce Tung, 23andMe's vice president of research, says her group plans to roll out surveys to the more than 80 percent of customers who have consented to be part of research. They hope to get hundreds of thousands of volunteers to enroll in the study, which will ask questions about their social distancing measures, symptoms, and COVID-19 test results.
Unique challenges of collecting genomic data during the pandemic
Every new positive case of COVID-19 provides another valuable data point for genomic studies. But if the pandemic wanes significantly, it is possible some studies may never be completed. "In some ways we're playing a weird game, because the best scenario would be if we can't get enough data because there weren't enough cases," says Tung.
For now, the rapidly moving nature of the pandemic, and the infection itself, poses unique challenges. For their study, Chung's and her colleagues have already identified thousands of positive cases, which they are consenting remotely. Several times, coordinators have called potential study subjects after they've been discharged, only to find out they've died.
Chung, who pivoted her own work on rare diseases to contribute to COVID-19 research, says she feels a tremendous sense of urgency. "We think about what we can learn in two weeks, not what we can learn in two years," says Chung. "Literally, my teams are working seven days a week, 16 hours a day."
The same issue that has hampered efforts to stem the spread of the coronavirus-the lack of widespread testing-is also complicating research to understand its biology. For instance, just this week, New York City added more than 3,700 people to its death toll who were presumed to have died of the coronavirus but had never tested positive. "If we don't have widespread testing, then I can't rely on that to tell me that someone was positive or not," says Duggal.
If scientists are successful in identifying genes that presage the infection's most devastating effects, they could more effectively triage the patients who need medical attention. If they get lucky, they might even uncover genes that make some people resistant, granting them the return to normalcy that so many people crave. So far, there's no evidence for this.
"I'm not convinced this is going to be the last one of these infectious disease crises," Chung says. "I think what we're trying to do is learn what we can for this one condition . . . and gain a better understanding of the immune response and generally how we fight infections."
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