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Wednesday Nite at the Lab – Isthmus

Posted: January 5, 2022 at 2:20 am

press release: For the fall semester, WN@TL goes hybrid both with Zoom and with in-person presentations. The zoom registration link is still go.wisc.edu/240r59. Starting September 15, you can also watch a live web stream at biotech.wisc.edu/webcams

On January 5, Jenyne Loarcaof the Department of Horticulture will use carrots to help us see more clearly the origins, the genetics, and the roles crops play in our lives and on our lands. Jenynes talk is entitled Genetic Diversity Matters: A Field Exploration of 695 Carrot Varieties."

Description: In this talk we'll explore humans' connection with preserving plant life. An impressive 70% of the food we eat is derivedfrom plants, and most plants are grown from seeds. As humans, we've had a deep connection with seeds throughout ourhistory. Humans have been saving and cultivating seeds for tens of thousands of years.

The first large-scale institutionalized practice of seed saving began with the first seed library only 125 years ago. TheU.S. gene bank carries seed from 695 rainbow carrot varieties, collected from 60 countries all around the world.Weused this diverse collection to study traits that are important to carrot growers and to determine the genetic basis ofthese traits.

Using carrots as a case-study, we will explore why the genetic diversity in this carrot collection isfoundational for vegetable breeders to create new varieties of carrot that are farmer-friendly and fun to eat.

We will explore the idea of seed as a genetic resource and seed-saving as genetic conservation work. We will discussthe importance of seed saving, the role that gardeners and researchers play in preserving genetic diversity, and theimportance of genetic diversity to climate resilience and our uncertain future.

Explore More: https://www.nature.com/articles/ng.3565

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The ghost wolves of Galveston island – The Indian Express

Posted: January 5, 2022 at 2:20 am

From a distance, the canids of Galveston Island, Texas, look almost like coyotes, prowling around the beach at night, eyes gleaming in the dark.

But look closer and oddities appear. The animals bodies seem slightly out of proportion, with overly long legs, unusually broad heads and sharply pointed snouts. And then there is their fur, distinctly reddish in hue, with white patches on their muzzles.

The Galveston Island canids are not conventional coyotes at least, not entirely. They carry a ghostly genetic legacy: DNA from red wolves, which were declared extinct in the wild in 1980.

For years, these genes have been hiding in plain sight, tucked away in the seemingly unremarkable animals that scavenged for food behind housing developments and roamed the grounds of the local airport.

Their discovery, which came after a determined local resident persuaded scientists to take a closer look at the canids, could help revive a captive breeding program for red wolves and restore the rich genetic variation that once existed in the wild population.

It doesnt seem to be lost any longer, said Bridgett vonHoldt, an evolutionary biologist at Princeton University, referring to the genetic diversity that once characterized red wolves. We might have a chance to bring it back.

They Just Didnt Look Right

Ron Wooten, a Galveston resident, never paid close attention to the local coyotes until they ran off with his dog one night in 2008. A pack took him and carried him off, recalled Wooten, an outreach specialist at the US Army Corps of Engineers.

He found the pack, and what remained of his dog, in a nearby field. He was horrified, and he blamed himself for his dogs death. But as his flashlight swept over the coyotes red muzzles, he found himself fascinated.

Determined to learn more, he posted a message on Facebook asking his neighbors to alert him if they spotted the animals. Eventually, a friend came through: There was a pack near her apartment building.

Wooten raced over with his camera, snapping photographs as he watched a group of pups chasing each other. They were just beautiful, he said.

But when he looked more carefully at the photos, he began to wonder whether the so-called coyotes were really coyotes at all. They just didnt look right, he said. I thought at first that they must have bred with Marmaduke or something because they had superlong legs, superlong noses.

Wooten, a former fisheries biologist, started reading up on the local wildlife and stumbled across the history of red wolves. Once abundant in the southeastern United States, the wolves had dwindled in number during the 20th century a result of habitat loss, hunting and other threats.

In the 1970s, the US Fish and Wildlife Service made a last-ditch effort to save the species, traveling along the Gulf Coast and trapping all the red wolves it could find. Scientists selected some of the animals for a breeding program, in hopes of maintaining the red wolf in captivity.

Wooten became convinced that the creatures that had taken his dog were actually red wolf-coyote hybrids, if not actual red wolves.

Eager to prove his hypothesis, he began looking for dead canids by the side of the road. I was thinking that if these are red wolves, then the only way theyre going to be able to tell is with genetics, he recalled.

He soon found two dead animals, collected a small patch of skin from each and tucked them away in his freezer while he tried, for years, to pique scientists interest.

Sometimes they wouldnt respond, he said. Sometimes theyd say, Yeah, thats a neat animal. Nothing we can do about it. And, Theyre extinct. Its not a red wolf.

Genetic Secrets

Eventually, in 2016, Wootens photos made their way to vonHoldt, an expert on canid genetics.

The animals in Wootens photos immediately struck her. They just had a special look, she said. And I bit. The whole thing hook, line and sinker.

She asked him to send his specimens, but there was a glitch: By then, he had lost one. So he packed up the skin tissue he could find and threw in the scalpel he had used to prepare the other sample, hoping that the scientists could extract DNA from it.

It was just a really kind of lovely chaos, vonHoldt said. (The scientists did manage to pull DNA from the scalpel, but Wooten later found the second sample and mailed that, too.)

VonHoldt and her colleagues extracted DNA from the skin samples and compared it to DNA from coyotes, red wolves, gray wolves and eastern wolves. Although the two Galveston Island canids were mostly coyote, they had significant red wolf ancestry; roughly 30 per cent of their genetic material was from the wolves, they found.

It was a real validation, I think, to the people on the ground the naturalists and the photographers on the ground saying, We have something special here, said Kristin Brzeski, a conservation geneticist who was a postdoctoral fellow in vonHoldts lab at the time. And they do.

Wooten was thrilled. It blew me away, he said.

Even more remarkable, some of the genetic variants, or alleles, the Galveston animals carried were not present in any of the other North American canids the researchers analyzed, including the contemporary red wolves. The scientists theorize that these alleles were passed down from the wild red wolves that used to roam the region.

They harbor ancestral genetic variation, this ghost variation, which we thought was extinct from the landscape, vonHoldt said. So theres a sense of reviving what we thought was gone.

The researchers suspect that some red wolves evaded the U.S. Fish & Wildlife Service dragnet back in the 1970s. There was surely a little slippery one that got away, or a couple, vonHoldt said.

At some point, the red wolves or their descendants bred with local coyotes and not just in Texas. In 2018, the same year vonHoldts team published its findings, another group documented high levels of red wolf ancestry in wild canids in Louisiana.

The findings could help scientists understand the genetic variation that once existed in wild red wolves and even resurrect it.

We can start actually understanding what was the historical red wolf and think about reconstructing that animal, said Brzeski, who is now at Michigan Technological University.

In the late 1980s, some of the red wolves from the captive breeding program were released in North Carolina. But that experimental population has plummeted in recent years; officials estimate that fewer than 20 of the animals now patrol the Carolina coast. And all the red wolves alive today are descended from about a dozen animals, an extremely low level of genetic diversity that could further imperil the species.

Hybrid Help

The hybrids raise new conservation possibilities. For instance, scientists might be able to restore genetic diversity by carefully breeding red wolves to hybrids with high levels of red wolf ancestry. Or they could use artificial reproductive technologies or gene-editing techniques to insert the ghost alleles back into red wolves, vonHoldt said.

The findings also come as some scientists have begun rethinking the value of interspecies hybrids. Oftentimes, hybridization is viewed as a real threat to the integrity of a species, which it can be, Brzeski said.

One reason that the red wolf populations declined in the wild is because the animals frequently interbred with coyotes. But, she added, here we have these hybrids that are now potentially going to be the lifeline for the highly endangered red wolves.

The discovery of hybrids in both Texas and Louisiana also suggests that scientists and officials may want to refocus their red wolf conservation efforts on those areas, said Lisette Waits, a conservation geneticist at the University of Idaho and co-author of the 2018 paper on the Louisiana hybrids.

In addition to studying the hybrids, it might make sense to reintroduce captive-bred red wolves to those regions, where animals with red wolf genes still roam the landscape. It could completely change the direction of the red wolf recovery program, Waits said.

Brzeski, vonHoldt and their collaborators are now studying the hybrids in both Texas and Louisiana as part of the new Gulf Coast Canine Project.

They are using GPS collars and wildlife cameras to learn more about the canids movements and behaviors, collecting fecal samples to analyze their diets, using genetic analysis to trace pack relatedness and collecting tissue samples from animals with the most red wolf ancestry. One goal, vonHoldt said, is to create a biobank set of specimens that could be used to help increase the genetic health of the captive red wolf population.

They are also hoping to learn more about how these red wolf alleles have persisted, especially in animals that live close to humans in a popular tourist destination. The island setting, which keeps the canids relatively reproductively isolated, is probably part of the explanation, but so is the lack of persecution, Brzeski said, noting that the animals were not commonly hunted.

Indeed, Wooten is not the only local resident who has taken an interest in the animals. The research team works closely with Josh Henderson, the animal services supervisor at the Galveston Police Department, and there is considerable community support for the canids.

Steve Parker, a lawyer who grew up in the area, remembers hearing childhood stories about his relatives trapping red wolves. The Galveston canids have helped him connect with the older generations, many of whom have passed away. Id like to see something and maybe be able to touch something that was special to them, he said.

Wooten, for his part, dreams of setting up an educational center devoted to teaching the public about the unique animals. The possibilities of what these animals hold down here is pretty valuable, he said. And thats the reason I pursued it, I think. I think God was thumping me on the head and saying, Hey, I got animals here. Take care of em.

This article originally appeared in The New York Times.

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3 COVID Stocks That Could Double in 2022 – The Motley Fool

Posted: January 5, 2022 at 2:20 am

The market's a forward-looking mechanism, and some people might feel that the COVID-19 pandemic is "over." That's probably an exaggeration. While vaccinations will hopefully reduce the danger, the virus will continue to mutate, and healthcare companies will continue to fight it. Read more to see why three Fool.com contributors think COVID stocks Fulgent Genetics(NASDAQ:FLGT),NRx Pharmaceuticals(NASDAQ:NRXP), andAdaptive Biotechnologies(NASDAQ:ADPT)could double your money this year.

Patrick Bafuma (Fulgent Genetics): Entering the last wave of 2021, you may have heard that there was a run on COVID tests. In fact, just this week, the local CVS told me that there was not an over-the-counter test available within 20 miles. Yet many countries, ports, and employers want the results of a PCR test within three days prior to entry. While this may put a strain on resources, it's great news for RT-PCR test maker Fulgent Genetics.

Image source: Getty Images.

This medical diagnostics company has focused on contracting with school systems, nursing homes, athletic organizations, health clinics, and the government to commercialize highly specific PCR testing for the SARS-CoV-2 virus. Having booked $95.5 million in revenue in the third quarter, it is likely safe to assume this will continue with the omicron variant well into the new year. Adjusted gross margin was a juicy 81.3% in Q3 2021, too. Over the last year, margin has floated between 77.1% and 82.6%, so aside from inflationary issues, I have little reason to think the margin will not remain enviable. And while it's clear that currently, the company's future remains tethered to COVID-19, it has also been clear that the virus refuses to go away. As such, I'm not convinced that COVID diagnostic numbers will melt away for the company. And with short interest now at just under 13%, positive results for the company could take shareholders on an enjoyable trip up and to the right.

With a price-to-earnings (P/E) ratio of just over 5, this stock looks insanely cheap. When compared to classic lab vendors like Laboratory Corporation of America Holdings and Quest Diagnostics, with P/E ratios of 10.9 and 10.2 respectively, or Abbott Laboratories and its Binax test at a P/E of about 35, Fulgent looks significantly undervalued. With a P/E in the mid-single digits and what seems like a never-ending need for its product, Fulgent Genetics could be an easy double in 2022.

George Budwell (NRx Pharmaceuticals): NRx Pharmaceuticals' stock shed an eye-popping 80.4% of its value over 2021. Although the drugmaker's shares initially popped during the first few months of 2021, Wall Street's enthusiasm for this speculative coronavirus stock steadily waned as the year progressed thanks to the U.S. Food and Drug Administration (FDA) declining to grant Emergency Use Authorization (EUA) for the company's severe COVID-19 treatment, Zyesami (aviptadil). The long and short of it is that Zyesami probably would have racked up several hundred million dollars in sales with an EUA for severe COVID-19 cases. That's a tremendous commercial opportunity for a company with market cap under $300 million at the time of this writing.

The good news is that NRx Pharmaceuticals recently filed a new Breakthrough Therapy Designation (BTD) request for Zyesami with the FDA. This revised BTD request centers around COVID-19 respiratory failure in patients who progress despite treatment with remdesivir and other approved therapies. If granted, this regulatory designation might open the door for an EUA in this patient population. While this revised target market is certainly smaller in scope, it would still amount to a healthy commercial opportunity for a company of NRx Pharmaceuticals' current size. In fact, NRx Pharmaceuticals ought to be able to bank at least $100 million in sales this year if the FDA gives the green light this time around.

The big picture is that this beaten-down coronavirus stock might be gearing up for a monstrous run higher in 2022.

Taylor Carmichael (Adaptive Biotechnologies): Adaptive Biotechnologies is focused on the immune system. The company is mapping 30 billion immune receptors in the human body and is using supercomputers fromMicrosoft to run the data as it maps our adaptive immune system. Later this decade, Adaptive says it could have a universal blood test on the market: A doctor will take a blood sample and be able to "hack" your immune system and see what diseases it is fighting. This blood test could reveal if you have infectious diseases, autoimmune disorders, or cancer.

In the meantime, Adaptive already has several diagnostic tests on the market. The FDA has cleared three of the company's clonoSEQ tests for minimal residual disease in blood cancers (multiple myeloma, acute lymphoblastic leukemia, and chronic lymphocytic leukemia). And the company has an EUA for its COVID-19 test.

Adaptive's COVID test is the first on the market that uses T cells in the blood to check for the disease. Just recently the Molecular Diagnostic Services Program agreed to pay $770 per test for certain groups of individuals, including immunocompromised patients.

Adaptive's not profitable yet, and its revenue is still meager: $146 million over the trailing 12 months. The stock is down 50% as impatient investors head for the exits. But that's a mistake. The company estimates there are 7 million immunocompromised patientsjust in the U.S. That's a $5 billion market opportunity in the near term. With the government paying for the tests, we should see a spike in Adaptive's COVID-related revenue in 2022, and the stock should jump along with it.

This article represents the opinion of the writer, who may disagree with the official recommendation position of a Motley Fool premium advisory service. Were motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.

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COVID-19 directly damages, creates scar tissue on the kidneys, study finds – WDAF FOX4 Kansas City

Posted: January 5, 2022 at 2:19 am

(StudyFinds.org) Although studies show COVID-19 is capable of infecting a patients kidneys, the viruss exact impact on the organs has been unclear until now. A team of German and Dutch scientists report COVID-19 causes direct cellular damage within the kidneys, contributing to tissue scarring.

Conducted at the RWTH Uniklinik Aachen in Germany and the Radboud University Medical Center in the Netherlands, study authors assessed and compared kidney tissues among COVID-19 ICU patients, other patients in the hospital for a non-COVID-related lung issue, and a group of healthy people. Results show kidney tissue from the COVID-19 patients showed much more tissue scarring than others.

The first phase of the investigation clearly established that COVID-19 damagesthe kidneys. Next, researchers set out to determine how the virus accomplishes this.

Many recent studies indicate that some of COVID-19s more severe symptoms emerge due to an overreaction of the bodys immune response and too much inflammation, not coronavirus itself. Is this the case for the kidneys as well, or is COVID-19 inflicting damage on these organs directly?

The team created a series ofmini kidneys, called organoids, by culturing them in a lab setting. Developed using stem cells, the organoids featured many different kidney cells, except immune cells. Researchers infect each organoid with COVID, allowing the team to observe the virus direct impact on kidney cells. Once again, scientists noted kidney organoid scarring as well as accompanied signals that contribute to the scarring process.

These findings strongly indicate that the coronavirus itself, notinflammationor any other systemic effects, is responsible for the observed kidney damage seen in COVID-19 patients.

In our study, we thoroughly investigated the causal damaging effects of the Coronavirus in the kidneys. The infected kidney organoids show that the virusdirectly causes cell damage, independent of the immune system. With this work, we found a piece of the puzzle showing the deleterious effects the virus can have in the body, says co-researcher Jitske Jansen in amedia release.

These conclusions are quite similar to the findings of another, larger American study encompassing over 90,000 COVID-19 survivors. Just like this work, that research found that reported declines in kidney functioning amongCOVID-19 patientsis likely due to the coronavirus itself.

Kidney fibrosis, or scarring, is a serious long-term consequence that can occur virtually after any injury to the kidney and correlates with kidney function. Our work shows kidney scarring in COVID-19 patients, which provides an explanation why the virus might cause kidney functional decline as demonstrated in other studies. Long-term follow-up studies will provide further insights into kidney-related pathologies caused by SARS-CoV-2, concludes co-researcher Katharina Reimer.

Thestudyis published in the journalCell Stem Cell.

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Clomid For Men On Testosterone Replacement Therapy (TRT …

Posted: January 5, 2022 at 2:17 am

IMH doctor discusses how to avoid fertility issues during testosterone replacement therapy

Marc DiJulio, MD, FACEP

You may be wondering about testosterone replacement therapy (TRT) and fertility issues. We know that TRT may reduce sperm production and impact fertility. Very simply, the pituitary gland in the brain is the director of testicular function. If it sees a high testosterone level, it stops telling the testes to produce testosterone. This also affects sperm production. This also explains why testes shrink a bit on TRT. That is why we use Human Chorionic Gonadotropin (HCG) in our TRT programs to periodically stimulate the testes. It reminds the testes that they do have a job to do other than just making testosterone.

Clomid (clomiphene citrate) uses a different approach to increase testosterone and spermatogenesis. It was originally developed and tested to increase ovulation and, thereby, improve fertility in women. The result in men is a modest improvement in testosterone levels while preserving sperm production. We can usually achieve a 100% increase in T levels with Clomid. In some cases, one may see up to a 200% increase. This increase is not as high as pellets or injections but it can make a big difference depending on how low you are. So if you had an initial level of 300, we would hope to see an increase to 600, +/-. Some clients may even see a larger increase.

DIAGNOSIS & TREATMENT OF LOW T

Clomid for men stimulates the bodys own production of testosterone. Clomid is a pill taken daily. It is generic and cheap. No shots. It does not interfere with the bodys checks and balances of testosterone. Fertility is preserved. No testicular shrinkage. It has few, if any, side effects and this is usually dose-related. Clomid, by increasing T levels, can produce the same/similar effects as traditional TRT. Each patient is different and the response will vary depending on current testosterone level. It is inexpensive and usually covered by health insurance.

In lower levels of testosterone, it takes longer to see the benefits of Clomid than with injection therapy. It may also not work, especially in patients over 60 and those with compound medical issues. Some patients may not see an increase in libido as Clomid does have some mild estrogenic properties. Of course, we follow the labs, just like in TRT, and would correct for an elevated estradiol level if needed (anastrozole). There have been rare reports of vision changes. If this happens, the patient should note very specifically what occurred, how long it lasted, etc. and then stop the Clomid until you speak with your doctor.

A typical candidate for Clomid is younger and planning on having children soon or in the future. Patients who just do not want to deal with injection or pellet therapy and are willing to accept a lower T level. Patients who have been on TRT and have decided to have children but want to maintain some increase in testosterone levels. Men who have known low sperm counts. Patients who have a varicocele (a problem with the blood vessel around the testes) that can cause infertility.

The fact that these conditions were also more prevalent in the older age group seems to indicate that the lack of clinical response may be the result of comorbid medical factors than of age alone.

The dosage range is 12.5mg 50mg per day. I prefer to start at 25mg every other day for a short trial period and then increase to daily dosing. Dosage can be adjusted based on any side effects, lab results, and an overall improvement in the T-effect. You will read any number of protocols that involve more complicated patterns of dosing. I prefer to keep it simple.

Some authors recommend taking Vitamin E to improve the success of Clomid. More than 400 iu is not recommended, a much smaller dose is fine.

It takes 90 to 108 days from the time that sperm is produced in the testicles until it is ejaculated. It takes time for a man to see fertility results from Clomid. As such, a man should not stop taking the medication unless there is no improvement by the fourth month of treatment.

Like traditional TRT, most physicians do not have a good understanding of TRT or even that Clomid is a treatment choice. Most doctors think about Clomid as a womans drug and do not want to prescribe off-label. It is generic and inexpensive so there is little or no advertising.

If you are considering Testosterone Replacement Therapy but worry about possible fertility issues, you can trust the experienced physicians at Innovative Men's Health clinic to restore your quality of life and minimize possible side effects of the therapy. Schedule a consultation with our doctor today.

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Testosterone Therapy Effects: What to Expect After …

Posted: January 5, 2022 at 2:17 am

Testosterone replacement therapy can sound a little like the fountain of youth. Replace lost levels of the hormone, travel back in time to your younger years?

As guys age, their levels of testosterone tend to decline. And thats a big problem: Testosterone binds to proteins throughout your body and brain called androgen receptors, which help control and regulate a whole range of different bodily functions, explains Ronald Tamler, M.D., Ph.D., associate professor of medicine at the Icahn School of Medicine at Mount Sinai.

If theres not enough testosterone to go around, those androgen receptors all over your body and brain stay silent, leading to symptoms like low libido, weak erections and orgasms, inability to build muscle mass, low energy, or just feeling a little blue. A condition called hypogonadism low testosteronedevelops when your body cant produce enough of it.

Related: 8 Sneaky Signs Your Testosterone Is Too Low

Thats where testosterone replacement therapya treatment that raises your low testosterone levelscomes in. Testosterone can be supplemented in the form of an injection, a gel, a suction cup on your gums, and even a deodorant. It comes down to personal preference and what your insurance covers, says Dr. Tamler.

Now, testosterone therapy is just for guys whose levels are actually low, usually under 300 nanograms per deciliter (ng/dl) on a blood test. If youre in the normal range, T-therapy isnt on the tableand wouldnt do you good anyway, he says.

If you are prescribed testosterone therapy, youll likely start to see some changes, big and small, pleasant and not-so-pleasant. You may not see them all, and they may not all appear right away, but here are 9 benefits and drawbacks of testosterone therapy you should watch for.

When youre low on testosterone, you might notice your sex drive begin to dip. Androgen receptors are located in the parts of your brain that influence sexual desire, so if you dont have enough T to activate them, you may notice a drop in wanting to get it on, says Abraham Morgentaler, M.D., the director of Men's Health Boston and author of Why Men Fake It: The Truth About Men and Sexand Testosterone for Life.

When you replace your lost testosterone, that can activate those androgen receptors in the part of your brain that controls desire. In fact, regaining a healthy sex drive is one of the biggest benefits of testosterone replacement therapy, says Dr. Morgentaler.

In addition to upping libido, T-therapy can possibly make your erections more satisfying, too. You need to have testosterone to work on the receptors in the penis to help it trap blood to keep it [erect], says Dr. Tamler. Receptors help steer that process, and if you dont have enough T then the process is impaired.

This isnt the only piece of the puzzle, thougherections also rely on healthy nerves and blood flow. So that means that testosterone therapy by itself isnt a cure for erectile dysfunction itself.

Related: 5 Ways Happy Couples Deal When Their Sex Drives Diverge

"Muscles are extremely responsive to testosteroneone of the most reliable things we see [when someone starts testosterone replacement therapy] is an increase in muscle mass," says Dr. Morgentaler.

This is because androgen receptors are found in muscle tissue, so testosterone activates them to stimulate growth. Of course, to make the most of this benefit, youll need to be doing your part by strength training as well.

In addition to an increase in lean muscle mass, some men report fat loss as well. While testosterone doesnt directly incite fat loss itself, part of it may be thanks to the uptick in muscle massthe more muscle you have, the higher your basal metabolic rate (or BMR) will be, which means your body will burn more calories at rest. (Want to max out the process even more? Try The 21-Day Metashred from Men's Health, the at-home workout plan that will help you build lean muscle and burn fat at the same time.)

Jed Kaminetsky, M.D., a clinical assistant professor in the department of urology at NYU Langone Medical Center also notes that this may be partially because testosterone improves overall motivation to get up and sweat it out, so if you're motivated to put in the work again, you'll see results.

Related: 7 Reasons You're Not Building As Much Muscle As You Could

"It's very common for men to come in with low T and one of their primary symptoms is fatigue," says Dr. Morgentaler. "And when we treat them, a lot of men will say that their energy has improved." Many men also report an improvement in the "brain fog" that can come along with low testosterone, adds Dr. Tamler.

While researchers aren't exactly sure how exactly testosterone plays a role in energy yet, Dr. Morgentaler says one of the thoughts is that it has an effect on your mitochondria, which produce energy within cells. This case isnt closed on this yet, but the theory is that "testosterone turns them on so they're more productive in terms of creating the energy that the cells need."

Dr. Tamler also notes that it may be tied back to androgen receptors as well. "If they don't get sufficient input, that can cause fatigue," he says. So bringing testosterone levels back up can help reverse this.

Related: The 8 Best Foods to Keep You Energized All Day Long

Similar to its effects on energy, experts don't have a definitive answer to why testosterone impacts mood so deeplyafter all, "the brain is a complicated thing," says Dr. Tamlerbut they do see it as a potential life-changing benefit.

"In some ways, the impact on mood is one of the most profound benefits of T that we see," says Dr. Morgentaler. "Not everybody has that, but when we see it, it's remarkable. In my practice, patients will say, 'Oh, my mood's OK, maybe I just feel a little bit tired or blah.' And they come back and they say things like, 'I wake up in the morning and I'm optimistic about my day. I haven't felt that way in years.'"

In fact, a 2012 study published in The Aging Male found that after 12 months of testosterone therapy, the percentages of guys with moderately severe to severe depression symptoms decreased from 17 percent to 2 percent.

And more recent research also backs that up: "The largest randomized control trial for T was just completed a year ago, called the T Trials, and it showed that men who received T had a greater improvement in mood than men who received placebo," notes Dr. Morgentaler.

Related: 7 Surprising Symptoms Of Depression In Men That Prove It's Not All About Sadness

This is one of the most common side effects of testosterone replacement theory.

Normally, when your pituitary gland senses that there's not enough testosterone in the bloodstream, it sends down a hormone called luteinizing hormone (LH) to signal your testicles to start producing more testosterone, and a hormone called follicle stimulating hormone (FSH) to signal sperm production.

Related: Why Your Balls Might Feel Like a Bag Of Worms

When you take outside testosterone, the pituitary gland gets the memo that there's enough T in your bloodstream, so it stops sending these signals. This essentially puts the testicles to sleep (read: little or no sperm and testosterone production), says Dr. Kaminetsky.

"Most of the size of the testicle is dedicated to making sperm, so when you're making less sperm, the testicles get smaller," says Dr. Morgentaler. This also means it can hamper fertility, acting like birth control, so if you're planning on having kids, testosterone replacement therapy isn't an option.

6 Things Every Man Should Know About His Penis:

And production doesn't always go back to normal afterwards, either says Dr. Kaminetsky. A 2017 study in Fertility & Sterility found that increasing age and longer length of T-therapy was linked to less chances of normal sperm recovery. (Here are 7things you do every day that might be messing with your sperm.)

Some people notice a little swelling in their feet and ankles because testosterone can encourages your body to hold onto excess fluid, says Dr. Morgentaler.

This isn't a big deal for most people, he says, and its more common to see it if you're taking a non-daily treatment like an injection, where you're getting a higher dose of T in one sitting. You may notice a pound or two of difference on the scale, but it should melt away after a few days.

Related: Tom Brady Drinks 25 Glasses Of Water a Day. Should You Drink That Much, Too?

Going on testosterone replacement therapy may change your skin typefor better or for worse, says Dr. Morgentaler.

Like other hormones, testosterone can increase oil production, which isn't necessarily a bad thing. It's important for healthy skin, so you may actually end up with a better complexion. However, too much oily buildup can lead to breakouts.

Thankfully, this isn't that common, says Dr. Morgentaler, and it's typically seen in men who have a history of acne. (If you shudder at the reminder of your teenage skin, this might be a more likely side effect.)

Similar to the fluid retention, this is mainly seen with treatments like injections, when you're getting a higher dose all at once.

Related: 5 Reasons You Still Get Acne As a Grown-Ass Man

In all menwhether youre taking T or notsome testosterone is converted into the hormone estradiol, a form of estrogen. And in men who have more breast tissue by nature, the T they're taking that's naturally converted into estradiol could stimulate this breast tissue to grow.

This is called gynecomastia, says Dr. Morgentaler, and it's relatively uncommonhe says he doesn't even see one case a year.

If this does happen, though, your doctor will likely stop treatment for a month or two to allow your breast tissue to go back to normal, and then start you back up with T along with a drug that blocks the conversion of testosterone to estradiol.

Related: How to Get Rid Of Man Boobs

Testosterone replacement therapy has traditionally come along with serious warning labels that your risk for heart attack, stroke, and prostate cancer could rise, but this is still very controversialand recent evidence has begun to debunk some of these fears.

In the case of heart attacks and strokes, the concern is that testosterone thickens blood because it binds to androgen receptors that stimulate bone marrow to produce more red blood cells. Thicker blood is linked to a greater risk of heart attack and stroke.

But there isn't strong evidence to connect these cardiac events to testosterone itself, and some more recent studies actually suggest that normal testosterone levels might actually protect against these risks, says Dr. Morgentaler.

One mechanism at play here could be that reduced body fat is linked to overall better health, and testosterone replacement therapy can encourage this, says Dr. Morgentaler. More research is needed, he says, and to be safe your doctor will monitor your red blood cell count throughout your treatment.

As far as prostate cancer goes, this is fuzzy, too. Because there are androgen receptors in the prostate, testosterone can make it grow. So if you already have an enlarged prostate that makes it difficult to urinate, testosterone could exacerbate the issue, says Dr. Tamler.

Related: Should You Get the PSA Test to Screen For Prostate Cancer?

If you have existing prostate cancer, theoretically, testosterone could make it grow in the same way, says Dr. Kaminetsky. However, there isn't evidence to suggest that T actually causes prostate cancer.

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Recap: Recent Updates in the Treatment of Nonmetastatic Castration-Resistant Prostate Cancer – Cancer Network

Posted: January 5, 2022 at 2:17 am

In a recent OncView discussion, Aaron Berger, MD, vice president and chief medical officer at Associated Urological Specialists in Chicago, Illinois, shared clinical experiences and perspectives regarding treatments of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Clinicians need to be aware of all the treatment options available in this space, as many FDA-approved indications have emerged in the past few years, Berger said.

Thereve been several new options for nonmetastatic castration-resistant prostate cancer to come to market, he noted. The first was enzalutamide [Xtandi] followed shortly thereafter by apalutamide [Erleada], and then most recently darolutamide [Nubeqa]. Weve used all of them in our advanced prostate cancer clinic, and its certainly an improvement over the previous options [such] as first-generation antiandrogen therapies.

Berger detailed his strategies for therapy selection in this patient population, including insights in baseline patient characteristics, clinical trial data, and toxicity profiles of each novel agent that guide his decisions.

Berger said his first consideration in a patient with nmCRPC is whether they need additional systemic therapy. Age, comorbidities, prostate-specific antigen (PSA) doubling time, and medication adherence are some of the factors that may incline a clinician to treat a patient with a newer antiandrogen medication.

Some of these patients have a lot of other [medical] issues, Berger said. If theyre not excited about another medication or are worried about [adverse] effects, we may just observe them, especially if their [PSA is] rising somewhat slowly.

Ultimately, the treatment goals in this setting are to prevent progression of disease from nonmetastatic to metastatic, as survival rates dramatically decrease in later stages of the disease. Typically, we will check PSA and testosterone levels every 3 months, Berger said. He noted that testosterone less than 50 ng/mL and a PSA doubling of 10 months or less was the threshold for administering medication to patients in clinical trials.

Thats not in the labeling for all these medications. You certainly can use the medication if their doubling time is 11 months or 12 months, but normally its [with a PSA doubling time of] 10 months or less were really focused on, he said.

For imaging in a patient with a significant PSA rise, Berger said he references the RADAR III guidelines, which recommend next-generation imaging techniques for detecting previously metastases (Table 1).

We would certainly consider doing conventional imaging initially, such as a CT scan or bone scan, and if its negative then we would likely continue observation, Berger said. I typically wouldnt wait until PSA is 5, 10, or 20 ng/mL and just keep doing conventional imagingwe would likely move on to doing next-generation imaging studies earlier. Some other factors that might motivate imaging sooner include pain in the back, hips, or legs; urinary symptoms; or obstructions in the kidneys.

Regarding the 3 available next-generation androgen receptor inhibitors that are available to treat patients in this setting, Berger said their mechanisms of action are similar but varying molecular sizes account for the biggest differences reflected in slightly different toxicity profiles.

Darolutamide typically has less in the way of central nervous system effectssuch as fatigue, light headedness, or dizzinessthan what we sometimes may see [with the other agents], Berger said. But mechanistically, they work very similar.

Regarding metastasis-free and overall survival (OS) rates, pivotal clinical trials that led to the approval of these agents reflect similar results. The design of the studies are very similar and the results of the studies are very similar, Berger said. Sometimes theres a reason why you may not use one versus the other, such as if a patient does have significant fatigue or has any other central nervous system issues [such as] gait abnormalities. Potentially, the darolutamide may be a better choice than enzalutamide or the apalutamide. But in my experience, theyre all tolerated pretty well.

Berger then explored data from the phase 3 PROSPER (NCT02003924), ARAMIS (NCT02200614), and SPARTAN (NCT01946204) trials that led to the approvals of enzalutamide, darolutamide, and apalutamide, respectively.

All 3 trials had very similar patient populations with a PSA doubling times of 10 months or less. All the patients had rising PSA that was confirmed on more than 1 occasion and castrate levels of testosterone less than 50 ng/mL, Berger said. They were all looking at metastasis-free survival as the primary end point.

At the initial readout of the SPARTAN trial, metastasis-free survival (MFS) was statistically significantly improved with apalutamide versus the placebo group (HR, 0.28; 95% CI, 0.23-0.36; P < .001).2 Similarly, MFS in PROSPER showed a 71% reduction in the risk of metastasis or death with enzalutamide compared with placebo (HR, 0.29; 95% CI, 0.24-0.35; P < .001).3 In ARAMIS, patients treated with darolutamide derived a significant treatment benefit versus those treated in the placebo group (HR, 0.41; 95% CI, 0.34-0.50; P < .001).4

In subsequent analyses, it is now borne out that they all do result in improvements in overall survival, Berger said. OS results with next-generation agents versus placebo were statistically significant for SPARTAN (HR, 0.78; 95% CI, 0.64-0.96; P = .016),5 PROSPER (HR, 0.73; 95% CI, 0.61-0.89; P = .001),6 and ARAMIS (HR, 0.69; 95% CI, 0.53-0.88; P = .003).7

When discussing toxicity, Berger detailed each in the context of which adverse effects were commonly associated with each agent.

We typically see with enzalutamide fatigue or asthenia. These patients are all on androgen deprivation therapy at baseline [and] they have low testosterone at baseline, which can certainly decrease their overall energy level to start with, Berger said. Adding the enzalutamide in some patients does zap their energy substantially to the point where some dont really feel like they have any motivation and dont want to get out of bed.

For these patients, Berger said a slight dose reduction can have a profound effect on their energy levels. For example, reducing the dosage by 25% or switching a patient from a 4-pill dose to a 3-pill dose may help a patients experience without significant effects on their overall disease outcomes.

With apalutamide, full body rash 2 to 3 months into treatment may occur but often can be managed with oral antihistamines or topical corticosteroids. Rarely, patients have a severe full body rash that requires discontinuation of therapy.

Theres also a slightly higher risk with apalutamide of hypothyroidism, but this is not typically something we screen for routinely, Berger said. Its mainly for those patients who have a history of hypothyroidism and are on medications already for thyroid replacement that well check a thyroid panel along with their PSA and testosterone.

Regarding darolutamide, Berger said its toxicity profile is likely the most favorable of the 3 available agents with its lower rate of fatigue, with most symptoms occurring during treatment.8 The bottom line is to know what to potentially expect and let the patients know what to be on the lookout for, he said.

Berger said comorbid conditions, such as obesity or diabetes, may inform the decision to administer an androgen inhibitor but they do not necessarily preclude a patient from treatment.

If they dont have significant cardiovascular issues and havent had a heart attacks, stroke, or congestive heart failure issues, Im not going to withhold a second-generation androgen inhibitor just because theyre a bit overweight, Berger said.

In fact, the relatively manageable safety profile of these agents means that treatment can be given without many dose adjustments even to patients with renal insufficiencies, he said.

Neurologic issues that may be present, such as unsteadiness, dizziness, or a history of falls should be taken into consideration, Berger said. Then the data would indicate that darolutamide may be a better option [because] there wasnt an increased risk from falls and fractures in the ARAMIS trial.

Regarding unmet needs in the treatment space, Berger said that guidance for prescribers on drug-drug interactions is lacking. There are a lot of medications patients are on, whether its antihypertensives, diabetes medications, or cardiovascular medications, especially the anticoagulants that may have some interactions with these medications. And the guidance, as far as what we can glean from the studies, is not always clear about whats safe and what may not be safe, he said.

Another consideration is whether nmCRPC will continue to be a disease state in the future, as next-generation imaging techniques become more prevalent in the treatment landscape and reveal metastasis in patients who would have been formerly considered nonmetastatic.

When you have a scan that can pick up an area of metastasis at [PSA of] 0.2 to 0.3 ng/mL, it may turn out that these patients are metastatic. All of these studies were done with conventional imaging, Berger said. The big question as far as this entire disease state is, will it still be a disease state 5 years from now?

Overall, Berger said clinicians shouldnt shy away from prescribing these medications to their patients, given their tolerability and ease of administration. I would not be afraid of these medications because you can easily add them into your clinical practice without a lot of trepidation, he said.

1. Crawford ED, Koo PJ, Shore N, et al. A clinicians guide to next generation imaging in patients with advanced prostate cancer (RADAR III). J Urol. 2019;201(4):682-692. doi:10.1016/j.juro.2018.05.164

2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

3. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. doi:10.1056/NEJMoa1800536

4. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

5. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. Eur Urol. 2021;79(1):150-158. doi:10.1016/j.eururo.2020.08.011

6. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892

7. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342

8. Gratzke CJ, Fizazi K, Shore ND, et al. Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial. Ann Oncol. 2021;32(suppl 5):S626-S677. doi:10.1016/annonc/annonc702.

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Department of Genetic Medicine | Johns Hopkins Medicine

Posted: January 5, 2022 at 2:16 am

The McKusick-Nathans Institute of Genetic Medicine and theDepartment of Genetic Medicineseekto further the understanding of human heredity and genetic medicine and use that knowledge to treat and prevent disease.

The Department of Genetic Medicineis working to consolidate all relevant teaching, patient care and research in human and medical genetics at Johns Hopkins to provide national and international leadership in genetic medicine. The Department of Genetic Medicineserves as a focal point for interactions between diverse investigators to promote the application of genetic discoveries to human disease and genetics education to the public. It builds upon past strengths and further develops expertise in the areas of genomics, developmental genetics and complex disease genetics. The Department of Genetic Medicineworks to catalyze the spread of human genetic perspectives to other related disciplines by collaboration with other departments within Johns Hopkins.

There are more than 300 dedicated employees in the Department of Genetic Medicine, fulfilling the Johns Hopkins tripartite mission of research, teaching and patient care. They include 45 full-time faculty, 15 residents, more than 70 graduate students and 200 staff.

All too often, when we see injustices, both great and small, we think, that's terrible, but we do nothing. We say nothing. We let other people fight their own battles. We remain silent because silence is easier. Qui tacet consentire videtur is Latin for 'Silence gives consent.' When we say nothing, when we do nothing, we are consenting to these trespasses against us.Roxane Gay

The indifferent and arrogant murder of George Floyd is but one of many searing examples of racism, oppression and sheer wickedness imposed on members of the African-American community over the last 400 years. Repeatedly, over these many years, periods of apparent progress have been undercut by horrific acts of racially-based evil that expose an underlying hard core of racial bias and systematic racism. The sadness, anger and frustration we all feel are compounded by the failure of our society to respond to these events with real and sustained justice. We cannot, however, let these events undermine our quest for meaningful and sustained progress towards correcting the systemic problems and beliefs leading to these events. To quote Martin Luther King Jr., Change does not roll in on the wheels of inevitability, but comes through continuous struggle.

How can we break out of this cycle of modest progress punctuated by horrific failures? The answers to this question are neither simple nor obvious. Success will require a sustained and multi-faceted effort from all of us. Some reactions seem obvious and personally attainable; we must treat all members of our society equally and fairly. In these difficult times, we much reach out to those directly affected with understanding, respect, and support. All of us must commit to and participate in these positive interactions. Beyond these responses of the moment, we must search for ways that we can change the social, economic and personal environment to minimize the likelihood of recurrence and maximize progress towards real equality for all. As geneticists, we treasure diversity and understand many of the biological factors underlying it. Perhaps, one special responsibility for us is to help others in society understand and value diversity and individuality.

As members of the Human Genetics program and Department of Genetic Medicine community, we recognize there are some among us who are more vulnerable to the biases illuminated by the death of George Floyd and many, many others; whose fear of an encounter with the police is amplified by personal and community experience; and whose experience of pain and suffering far exceeds what most of us can fully understand. To those most vulnerable in our Department of Genetic Medicinefamily, we stand with you and raise our voices to support you. We are ready to listen and act in pursuit of a learning environment of which you can be proud and a world into which you will move and feel free to change.

Finally, as we search for appropriate responses, we are grateful to have your voices, your guidance to help illuminate a path forward. We recognize and are encouraged by the outpouring of activism, passion, rage and love from our students, our department, our community and even our own families. We also recognize that this journey, which began centuries ago, will be long, sometimes uncomfortable and inelegant and studded with setbacks. We are, however, committed to do everything in our power to speed its progress.

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Harnessing The Human Virome For The Next Generation Of Gene Therapy Vectors – Clinical Leader

Posted: January 5, 2022 at 2:16 am

By Tuyen Ong, MD, MBA, Ring Therapeutics and Flagship Pioneering

We spend so much time thinking about viruses that cause disease, especially over the last two years, but have you ever considered the fact that not all viruses are harmful? What if we could harness the power of relatively harmless viruses to solve major obstacles in medicine? For the first time ever, researchers are focusing on growing our understanding of a relatively understudied class of harmless viruses that live within all humans and could be the answer to many questions in genetic medicine.

Since its discovery, the human microbiome has served as a rich source of therapeutics and medical insights,1-3 but a lesser-known component of the microbiome, the virome, can potentially offer solutions to problems that face medicine today. The human commensal virome is composed of a plethora of viruses that live harmoniously within all of us.4 These commensal viruses often have broad tropisms, inhabiting a wide range of tissues, such as our eyes, hearts, and livers, all the while subverting the immune response that accompanies foreign viral infections.

Throughout history, researchers have discovered how to transform foreign viruses into life-saving therapies. This began as vaccines in which viral material prepares the immune system to fight a future infection and even led to using viruses to fight certain cancers. But one of the most recent advancements in using foreign viruses to fight human disease is gene therapy engineering viruses to replace or fix genetic defects. Though as game-changing as these viral-based gene therapies are, many barriers still limit their therapeutic potential.

Since the first U.S.-approved therapy for a genetic disease in 2017,5 researchers began ushering in an era of treatment possibilities for those with debilitating genetic diseases using foreign viral vectors.

Viral vectors use the capsid of a virus to encapsulate and deliver genetic cargo to the cell nucleus, and because viruses are so effective at entering host cells, they quickly became standard.6-7

The most common viral vectors in gene therapy today are adeno-associated viruses (AAVs), non-enveloped viruses belonging to the parvovirus family discovered in the 1960s.8-9 At the outset, AAVs were promising, offering a potential delivery vehicle that was tractable and relatively safe in preclinical models. Additionally, the viral biology of AAVs suggested prolonged safety profiles that would largely avoid mutagenesis, a likely result if the genetic material integrated within the host genome. Although some genomic integration has been observed in animal models,10-11 the AAV vector cargo largely remains as an episomal element within the nucleus, a positive in that theres less risk of insertional mutation but with a complementary downside whereby the cargo is diluted as cells grow and divide. This dilution requires redosing of the gene therapy in any tissue with dividing cells. However, once injected, the formation of neutralizing antibodies against the foreign AAV viral vectors has prevented safe redosing and resulted in the need for large, and often toxic, initial doses to be effective. These toxic doses have at times resulted in tragic outcomes in clinical trials.12-13 Additionally, natural prevalence of neutralizing anti-AAV antibodies in large proportions of the population (>40% in some serotypes14) precludes some patients from receiving even an initial dose of AAV-driven gene therapy.

Lentiviral vectors, a spherical enveloped RNA retrovirus, are another common viral vector in gene therapy today. Lentiviruses elicit a relatively weak immune response in animal models,15-16 and recent engineering successes have enhanced transduction of specific cell types.17 However, they are integrating viral vectors, which can provide long-term transgene expression, but also have a much higher risk of oncogenesis as a result of integration.18

Although viral vectors remain an ideal model for delivering genetic cargo because of their ability to efficiently enter host cells, the immunogenicity of AAVs and other vectors is a significant hurdle. The ideal viral vector platform would not elicit an immune response, would be potent, and would be diverse enough to infect targeted tissue types selectively.

The commensal virome may hold the solution. Recent research has shown how it may solve some of the greatest challenges remaining that are preventing the promise of gene therapy from reaching its full potential as a truly transformative treatment option.

Advances in metagenomic sequencing have revealed insights into the human virome with boundless value for gene therapy researchers. This includes exploring the diversity of a family of small commensal viruses called anelloviruses that have never been associated with disease.19-20

Almost every human maintains a diverse community of anelloviruses, called the anellome, that makes up the largest family of eukaryotic viruses within the human commensal virome.21

Anellovirus genomes do not integrate into the human genome, exhibit a broad yet specific tropism, and do not elicit a robust immune response, which allows them to persist in us for months or even years.19,22 These key facets make anelloviruses a promising new tool in our effort to overcome todays limitations in genetic medicine.

Anelloviruses are highly prevalent in humans, and many individuals often harbor a unique and dynamic anellovirus landscape.23 Additionally, a recent blood transfusion study utilizing our platform showed that anelloviruses are extremely diverse, highly transmissible, and persistent, with donor anelloviruses detected in recipients more than 200 days post transfusion (the last time point of data collection).23

Not only were anelloviruses shown to be both transmissible and persistent, but evidence also suggests that they are redosable. Despite significant genomic similarity between anelloviruses of recipients and donors, the anelloviruses from both donor and recipient co-exist within the recipient without causing any neutralizing immune response for an extended period of time.23 This critical facet of anellovirus biology could finally permit redosing of a viral vector in gene therapy.

Building on this data, Ring scientists set out to harness the unique anellovirus biology for therapeutic application. For a newly identified anellovirus genome, the team can recreate it in vitro as a fully synthesized recombinant human anellovirus, then recover it using traditional viral purification methods, marking the first time human anelloviruses have been produced in vitro.24

These recombinant anelloviruses can also be vectorized, loading the anellovirus capsid with chosen DNA cargo that can be successfully transduced into human cells in vitro.24 Ring dubs this novel viral vector an Anellovector.

Although natural anelloviruses do not elicit a robust immune response, the question remained whether humans maintain immunity against synthesized Anellovectors. Similar to natural anelloviruses and to no surprise to the Ring team, preclinical studies of its initial Anellovectors identified low preexisting immunity against it in a pool of thousands of human donor sera,24 validating the potential utility of Anellovectors as the next generation of gene therapy vectors.

Anellovectors harness the unique biology of human anelloviruses and have strong therapeutic potential because of five key features:

Anelloviruses are ubiquitous within the human body and, having co-evolved with humans for millennia, largely avoid triggering any significant immune reactions. Transfusion of similar anelloviruses between human patients showed persistence without a deleterious immune response.23 Through harnessing the unique feature of immune stealth of anelloviruses, Anellovectors have the potential to treat patients requiring redosing, such as those suffering from spinal muscular atrophy and hemophilia.

Greater than 40% of patients maintain a natural prevalence of some serotypes of anti-AAV neutralizing antibodies,14 precluding them from receiving even an initial dose of any AAV-driven gene therapy. Because humans maintain low preexisting immunity to anelloviruses and Anellovectors, their use may offer the opportunity for these patients to receive a potentially life-saving gene therapy treatment.

Many tissue types are elusive to current gene therapy vectors and are deemed unreachable. However, anelloviruses exhibit a broad tissue tropism, being found from head to toe of most humans,19 including those that are currently unreachable. Therefore, Anellovectors can be designed through harnessing specific anelloviruses that exhibit a targeted tropism. This specificity opens the door for potential solutions to a broad range of genetic diseases across tissue types, including the liver, offering a safer option with no hepatotoxicity.

Current virus-based gene therapy platforms, including some instances with AAVs, can randomly integrate within the human genome, disrupting the function of important genes and sometimes even causing oncogenesis. As with anelloviruses, Anellovector cargos remain as episomes in the nucleus and do not affect the host genome, minimizing the potential risk and making for a safer form of gene therapy.

Because Anellovectors can be synthesized and vectorized, Anellovectors can be engineered to accommodate a wide variety of therapeutic modalities, from single-stranded DNA for gene therapies to potentially enabling delivery of larger DNA products through packaging of mRNA.

Through a better understanding of the commensal virome, theres hope for a brighter future for gene therapy. This promising new technology may help gene therapy reach its full potential by overcoming the current limitations with repeat dosing, toxicity, and limited tropism.

Rings research team has uncovered and characterized the worlds largest collection of commensal anelloviruses and is harnessing those best suited for specifically targeting a wide array of diseases with significant unmet needs. The unique biology of anelloviruses may indeed provide a foundation for an unparalleled new gene therapy platform and the resulting new class of genetic medicines.

References

About The Author:

Tuyen Ong, MBA, MD, is CEO of Ring Therapeutics and CEO/Partner of Flagship Pioneering. He is a physician and bioentrepreneur. Prior to joining Ring Therapeutics in 2020, he served as senior vice president at Biogen and as Chief Development Officer at Nightstar Therapeutics until its acquisition by Biogen. During this time, he was involved with the companys public listing on the NASDAQ, corporate and gene therapy strategy, investor, and M&A activities. Ong brings more than 20 years of clinical and drug development experience from both large pharma and biotech, working in the fields of genetics, ophthalmology, and rare disease at PTC Therapeutics Inc., Bausch and Lomb Inc., and Pfizer. He is a member of the Royal College of Ophthalmologists and a Churchill Fellow.

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A rare gene mutation in Black patients is associated with early-onset heart failure – WFYI

Posted: January 5, 2022 at 2:16 am

New research finds a strong association between a rare genetic mutation and early-onset heart failure and hospitalization among Black Americans.Researchers found Black patients who develop heart failure and carry this genetic mutation develop the condition four years earlier than those not carrying it.

Dr. Ambarish Pandey, co-author of the study and assistant professor of internal medicine at the University of Texas Southwestern Medical Center, said the study raises the question: Should Black Americans be screened for this genetic mutation?

That's a question that I cant answer in just one study, he said. But I think it raises this broader question of: Is there benefit in screening for this abnormal mutation in Black patients, particularly in those who may be identified early on and can benefit from more aggressive risk modification for things like blood pressure control and other factors that contribute to risk of heart failure?

The genetic mutation known as TTR V142I allows protein to build up inside the heart, which can make it harder for the heart to contract and relax. That eventually can cause part of the organ to die a condition known as transthyretin amyloid cardiomyopathy.

Several prior studies linked the genetic mutation to this condition, but those studies did not explore the association with adverse clinical outcomes, including heart failure and hospitalization rates, Pandey said.

Researchers followed thousands of study participants for 12 years

This new study is the first to look at an exclusively Black cohort, he said. Thats significant because the genetic mutation is much more prevalent in people of African descent.

Pandey, along with researchers at several U.S. medical schools, followed a cohort of nearly 3,000 people of African descent over a period of 12 years and identified more than 200 patients who developed heart failure. The researchers found people with the mutation who experienced heart failure were more likely to have negative health outcomes, including early-onset heart failure, heart muscle injury and hospitalization.

Heart failure occurs when the heart cant pump enough blood to the bodys vital organs. Without close monitoring and management, the condition can be lethal. More than 6 million Americans are living with heart failure, according to the U.S. Centers for Disease Control and Prevention.

Health issues like obesity, high blood pressure and diabetes can increase a persons risk of heart failure. African Americans have higher rates of heart failure, hospitalization and death from the disease, according to national data.

This study was done on Black Americans participating in the Jackson Heart Study the longest and largest study looking at cardiovascular disease in Black Americans. The researchers followed the participants from 2005 to 2016. The process included heart imaging and blood tests.

Among the other significant findings: Even when heart imaging didnt turn up evidence of injury to the organ in study participants with the genetic mutation, blood tests that look for troponin, a marker of tissue damage, did. Those with the genetic mutation had significantly higher amounts of this protein in their blood.

The study opens a new avenue of investigations to further develop drugs and treatments, even prevention for patients [who] have this genetic predisposition to disease, said Dr. Patrice Desvigne-Nickens, program director at the National Heart, Lung and Blood Institute, which funded the research.

Desvigne-Nickens, who was not part of the study, said there are FDA-approved treatments that prevent heart failure when the heart begins to show signs of damage. But it remains unknown whether someone who carries the genetic mutation, but does not yet have abnormal amyloid protein deposits, could reduce their risk of heart failure by receiving those treatments.

Still, Desvigne-Nickens said these findings suggest that patients who already have heart disease may benefit from genetic testing.

If a Black patient is found to have this mutation, their physician and providers need to carefully monitor for signs and symptoms of heart failure, she said. Additionally, because this is a genetic marker, family members of patients with this mutation may also benefit from getting tested.

More research and improved health care access needed

Pandey said further research is needed before genetic testing is recommended for all people of African descent. He said in order to improve health outcomes, increasing access to genetic testing isnt the most pressing issue.

Access to care is a big issue in Black communities, Pandey said. So, forget about implementing genetic testing for amyloidosis. I think if I had to pick what to improve access to, I would improve access to blood pressure control, diabetes control, and things that are more prevalent and more common, and also associated with the risk of heart failure just as much.

Researchers dont know why this genetic mutation exists almost exclusively in patients of African descent. The vast majority of peoples genetic composition is consistent across races. But some genetic mutations show up with greater frequency among certain populations.

Population genetics and origins are important, because there is a selection having to do with your environment that determines the frequency of certain genes and variations, Desvigne-Nickens said.

For instance, the sickle cell trait a genetic trait that can cause sickle cell anemia, a blood condition that primarily affects people of African descent seems to be related to the prevalence of malaria in Africa.

Still, Desvigne-Nickens said the role genetic variations play in peoples health is far less significant than environmental factors. Long-standing socioeconomic and disparities in health care access facing Black Americans are among the contributing factors to many health conditions, she said.

The majority of the largest contributors to how long you live, and how healthy your life is, have to do with your behavior and the environment in which you live, she said. So, genetic testing doesn't absolve you of responsibility for healthy habits, healthy living and making sure that the environment is not hostile.

Desvigne-Nickens said this study is one type of precision medicine, which considers a persons genetics, environment and lifestyle to inform potential treatments. The approach could help address long-standing health disparities and the participation of African American patients makes this possible.

A real shout out to them, the participants. These are African Americans [who] participate in these studies and allow themselves to be tested because that information then can be used to help them, she said. Research is not something that has been welcome in communities of color, because research in the past has represented some level of exploitation and breach of trust for a variety of reasons.

As a physician of color herself, Desvigne-Nickens said better representation in medical and research spheres would help cultivate more trust and participation of communities of color in crucial research.

This story comes from a reporting collaboration that includes the Indianapolis Recorder and Side Effects Public Media a public health news initiative based at WFYI. Follow Farah on Twitter: @Farah_Yousrym.

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