Category Archives: Gene Medicine

ANI | Updated: Apr 26, 2020 22:08 IST

Washington D.C. [USA], April 26 (ANI): In a new discovery, scientists have found the protein that is responsible for helping the human heart heal.A group of scientists from the UT Southwestern Medical Center scientists have discovered a protein that works with other proteins during development to put the brakes on cell division in the heart and helps it to heal.The research was published in the journal-Nature.The findings could eventually be used to reverse this developmental block and help heart cells regenerate, offering a whole new way to treat a variety of conditions in which heart muscle becomes damaged, including heart failure caused by viruses, toxins, high blood pressure, or heart attacks.Current pharmaceutical treatments for heart failure - including ACE inhibitors and beta blockers - center on trying to stop a vicious cycle of heart muscle loss as strain further damages remaining heart muscle, causing more cells to die, explains UT Southwestern physician-researcher Hesham A. Sadek, M.D., Ph.D., a professor of internal medicine molecular biology, and biophysics. There are no existing treatments to rebuild heart muscle.Nine years ago, Sadek and his colleagues discovered that mouse hearts can regenerate if they're damaged in the first few days of life, spurred by the division of cardiomyocytes, the cells responsible for a heart's contractile force.However, this capacity is completely lost by 7 days old, an abrupt turning point in which division of these cells dramatically slows and the cells themselves enlarge. The reasons why these cells gradually slow and stop dividing has been unclear.Sadek and his team discovered in 2013 that a protein called Meis1, which falls into a category known as transcription factors that regulate the activity of genes, plays a key role in stopping heart cell division.However, he explains, although deleting this gene in mice extends the window of heart cell division, this effect is transient - heart cells missing this gene eventually slow and stop their multiplication.Consequently, the researchers wondered whether there were redundant mechanisms in place that stop heart cell division even when Meis1 is absent. Toward that end, they looked to see what other transcription factors might track activity with Meis1 in heart cells as they rapidly divide and then slow to a halt in the days after birth.They quickly discovered one called Hoxb13 that fit the bill. Other proteins in the Hox family, Sadek notes, have been shown to act as chaperones to Meis1 in other types of cells, ferrying Meis1 into the cell nucleus.To better understand Hoxb13's role in heart cells, the researchers genetically engineered mice in which the gene that codes for Hoxb13 was deleted. These mice behaved much like those in which just the gene for Meis1 was deleted - the window for heart cell rapid division was increased but still closed within a few weeks.When the researchers shut off Hoxb13 in adult mouse hearts, their cell division had a brief resurgence, enough to prevent progressive deterioration after an induced heart attack but not enough to promote significant recovery.However, when the researchers deleted both the genes for Meis1 and Hoxb13, heart cells in these mice appeared to revert to an earlier stage in development, both decreasing in size and multiplying more. After an induced heart attack, these mice had a rapid improvement in the amount of blood each beat could expel from the heart. Their heart function had almost returned to normal.With clear evidence that Meis1 and Hoxb13 work together to stop heart cell division in the days after birth, Sadek and his colleagues looked for what might in turn regulate these proteins. Their experiments suggest that the answer is calcineurin, a protein that's responsible for regulating the activity of other proteins by removing their phosphate groups.Because calcineurin plays a key role in a variety of diseases and other medical conditions, such as rheumatic arthritis, schizophrenia, diabetes, and organ transplant, several drugs already exist on the market that target this protein.Conceivably, says Sadek, other drugs could be developed to directly target Meis1 and Hoxb13. Researchers may eventually be able to develop strategies to restart heart cell division through a single drug or combinations that target any part of this regulatory pathway, he adds."By building up the story of the fundamental mechanisms of heart cell division and what blocks it. We are now significantly closer to being able to harness these pathways to save lives," Sadek said. (ANI)

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Researchers find a protein that helps heart heal - ANI News

TOPSHOT An aerial view shows the P4 laboratory at the Wuhan Institute of Virology in Wuhan in Chinas central Hubei province on April 17, 2020. The P4 epidemiological laboratory was built in co-operation with French bio-industrial firm Institut Merieux and the Chinese Academy of Sciences. The facility is among a handful of labs around the world cleared to handle Class 4 pathogens (P4) dangerous viruses that pose a high risk of person-to-person transmission. (Photo by Hector RETAMAL / AFP) (Photo by HECTOR RETAMAL/AFP via Getty Images)

An unprecedented amount of research has been focused solely on understanding the novel coronavirus that has taken nearly 150,000 lives across the globe. And while scientists have gotten to know some of the most intimate details of the virus called SARS-CoV-2, one question has evaded any definitive answers Where did the virus come from?

Live Science contacted several experts, and the reality, they said, is that we may never know where this deadly coronavirus originated. Among the theories circulating: ThatSARS-CoV-2 arose naturally, after passing from bats to a secondary animal and then to humans; that it was deliberately engineered and then accidentally released by humans; or that researchers were studying a naturally-occurring virus that subsequently escaped from a high-security biolab, the Wuhan Institute of Virology (WIV) in China. The head of the lab at WIV, for her part, has emphatically denied any link to the institute.

Just today (April 18), the vice director of WIV Zhiming YuanCGTN, the Chinese state broadcaster, said there is no way this virus came from us,NBC News reported. We have a strict regulatory regime and code of conduct of research, so we are confident.

Furthermore, thenotion that SARS-CoV-2 was genetically engineeredis pure conspiracy, experts told Live Science, but its still impossible to rule out the notion that Chinese scientists were studying a naturally-occurring coronavirus that subsequently escaped from the lab. To prove any of these theories takes transparent data and information, which is reportedly not happening in China, scientists say. Several experts have said to Live Science and other media outlets have reported that the likeliest scenario is that SARS-CoV-2 is naturally occurring.

Related:13 coronavirus myths busted by science

Based onnodata, but simply [a] likely scenario is thatthe virus went from bats to some mammalian species, currently unknown despite speculation, [and] spilled over to humans, said Gerald Keusch, associate director of the Boston University National Emerging Infectious Diseases Laboratories. This spillover event may have happened before the virus found its way into a live animal market, which then acted as an amplifying setting with many more infections that subsequently spread and the rest is history, Keusch said. The timeline is fuzzy and I dont think we have real data to say when these things began, in large part because the data are being held back from inspection, Keusch told Live Science.

The SARS-CoV-2 virus is most closely related tocoronavirusesfound in certain populations of horseshoe bats that live about 1,000 miles (1,600 kilometers) away in Yunnan province, China. The first known outbreak of SARS-CoV-2 in humans occurred in Wuhan and initially was traced to a wet seafood market (which sold live fish and other animals), though some of the earliest cases have no link to that market, according to research published Feb. 15 in the journalThe Lancet.

Related:11 (sometimes) deadly diseases that hopped across species

Whats more, despite several proposed candidates, from snakes topangolinsto dogs, researchers have failed to find a clear intermediate host an animal that would have served as a springboard for SARS-CoV-2 to jump from bats to humans. And if horseshoe bats were the primary host, how did the bat virus hop from its natural reservoir in a subtropical region to the bustling city of Wuhan hundreds of miles away?

These questions have led some people to look elsewhere in the hunt for the viruss origin, and some have focused on the Wuhan Institute of Virology (WIV).

In 2015, WIV became Chinas first lab to reach the highest level of bioresearch safety, or BSL-4, meaning the lab could host research on the worlds most dangerous pathogens, such as Ebola and Marburg viruses. (SARS-CoV-2 would require a BSL-3 or higher, according to the Centers for Disease Control and Prevention.) Labs like these must follow strict safety guidelines that include filtering air, treating water and waste before they exit, and requiring lab personnel to shower and change their clothes before and after entering the facility,Nature News reported in 2017.

These types of labs do spur concerns among some scientists who worry about the risks involved and the potential impact on public health if anything were to go wrong, Nature News reported.

Related:The 12 deadliest viruses on Earth

WIV was not immune to those concerns. In 2018, after scientist diplomats from the U.S. embassy in Beijing visited the WIV, they were so concerned by the lack of safety and management at the lab that the diplomats sent two official warnings back to the U.S. One of the official cables, obtained byThe Washington Post, suggested that the labs work on bat coronaviruses with the potential for human transmission could risk causing a new SARS-like pandemic, Post columnistJosh Roginwrote.

During interactions with scientists at the WIV laboratory, they noted the new lab has a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory, the officials said in their cable dated to Jan. 19, 2018.

When reports of the coronavirus first popped up in China, the U.S. Deputy National Security Advisor Matthew Pottinger reportedly suspected a potential link to China labs. In mid-January, according to a New York Times report, Pottinger asked intelligence agencies like the C.I.A., particularly individuals with expertise on Asia and weapons of mass destruction, to investigate this idea. They came up empty-handed, the Times reported.

Meanwhile, the lab at the center of these speculations had long been sounding the alarm about the risk of the SARS-like coronaviruses they studied to spawn a pandemic.

The head of the labs bat-coronavirus research, Shi Zhengli, published research on Nov. 30, 2017 in the journalPLOS Pathogensthat traced the SARS coronavirus pandemic in 2003 to a single population of horseshoe bats in a remote cave in Yunnan province. The researchers also noted that other SARS-like coronaviruses discovered in that cave used the ACE2 receptor to infect cells and could replicate efficiently in primary human airway cells, they wrote. (Both SARS and SARS-CoV-2 use the ACE2 receptor as the entry point into cells.)

Zhengli and her colleagues stressed the importance of monitoring and studying the SARS coronaviruses to help prevent another pandemic.

Thus, we propose that monitoring of SARS-CoV evolution at this and other sites should continue, as well as examination of human behavioral risk for infection and serological surveys of people, to determine if spillover is already occurring at these sites and to design intervention strategies to avoid future disease emergence, they wrote.

Related:20 of the worst epidemics and pandemics in history

The WIV lab, along with researchers in the U.S. and Switzerland, showed in 2015 the scary-good capability of bat coronaviruses to thrive in human cells. In that paper, which was published in 2015 in the journalNature Medicine, they described how they had created a chimeric SARS-like virus out of thesurface spike protein of a coronavirusfound in horseshoe bats, called SHC014, and the backbone of a SARS virus that could be grown in mice. The idea was to look at the potential of coronaviruses circulating in bat populations to infect humans. In a lab dish, the chimeric coronavirus could infect and replicate in primary human airway cells; the virus also was able to infect lung cells in mice.

That study was met with some pushback from researchers who considered the risk of that kind of research to outweigh the benefits. Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, was one of those scientists. Wain-Hobson emphasized the fact that this chimeric virus grows remarkably well in human cells, adding that If the virus escaped, nobody could predict the trajectory,Nature News reported.

None of this can show the provenance of SARS-CoV-2.

But scientists can start to rule out an idea that the pandemic-causing coronavirus was engineered in that lab or further created as a bioweapon. Researchers say the overwhelming evidence indicates this is a natural-borne virus that emerged from an animal host, likely a bat, and was not engineered by humans.

Related:28 devastating infectious diseases

This origin story is not currently supported at all by the available data, said Adam Lauring, an associate professor of microbiology, immunology and infectious diseases at the University of Michigan Medical School. Lauring pointed to a study published March 17 in the journalNature Medicine, which provided evidence against the idea that the virus was engineered in a lab.

In that Nature medicine study one of the strongest rebukes of this idea Kristian Andersen, an associate professor of immunology and microbiology at Scripps Research, and his colleagues analyzed the genome sequences of SARS-CoV-2 and coronaviruses in animals. They found that a key part of SARS-CoV-2, the spike protein that the virus uses to attach to ACE2 receptors on the outsides of human cells, would almost certainly have emerged in nature and not as a lab creation.

This analysis of coronavirus genome sequences from patients and from various animals suggests that the virus likely arose in an animal host and then may have undergone further changes once it transmitted and circulated in people, Lauring told Live Science.

That may rule out deliberate genetic engineering, but what about other scenarios that point to bats as the natural hosts, but WIV as the source of the outbreak?

Although researchers will likely continue to sample and sequence coronaviruses in bats to determine the origin of SARS-CoV-2, you cant answer this question through genomics alone, said Dr. Alex Greninger, an assistant professor in the Department of Laboratory Medicine and an assistant director of the Clinical Virology Laboratory at the University of Washington Medical Center. Thats because its impossible to definitively tell whether SARS-CoV-2 emerged from a lab or from nature based on genetics alone. For this reason, its really important to know which coronaviruses were being studied at WIV. It really comes down to what was in the lab, Greninger told Live Science.

However, Lauring said that based on the Nature Medicine paper, the SARS-CoV-2 virus has some key differences in specific genes relative to previously identified coronaviruses the ones a laboratory would be working with. This constellation of changes makes it unlikely that it is the result of a laboratory escape,' he said.

As for what viruses were being studied at WIV, Zhengli says she did a thorough investigation. When she first was alerted to the viral outbreak in Wuhan on the night of Dec. 30, 2019, Zhengli immediately put her lab to work sequencing the genomes of SARS-CoV-2 from infected patients and comparing the results with records of coronavirus experiments in her lab. She also looked for any mishandling of viral material used in any experiments,Scientific American reported. She didnt find any match between the viruses her team was working with from bat caves and those found in infected patients. That really took a load off my mind, she told Scientific American. I had not slept a wink for days.

At the beginning of February, Zhengli sent a note over WeChat to reassure her friends that there was no link, saying I swear with my life, [the virus] has nothing to do with the lab,the South China Morning Post reported Feb. 6. Zhengli and another colleague, Peng Zhou, did not reply to a Live Science email requesting comment.

The Wuhan lab does work with the closest known relative of SARS-CoV-2, which is a bat coronavirus called RaTG13, evolutionary virologist Edward Holmes, of the Charles Perkins Center and the Marie Bashir Institute for Infectious Diseases and Biosecurity at the University of Sydney, said in a statement from the Australian Media Center. But, he added, the level of genome sequence divergence between SARS-CoV-2 and RaTG13 is equivalent to an average of 50 years (and at least 20 years) of evolutionary change. (That means that in the wild, it would take about 50 years for these viruses to evolve to be as different as they are.)

Though no scientists have come forth with even a speck of evidence that humans knowingly manipulated a virus using some sort of genetic engineering, a researcher at Flinders University in South Australia lays out another scenario that involves human intervention. Bat coronaviruses can be cultured in lab dishes with cells that have the human ACE2 receptor; over time, the virus will gain adaptations that let it efficiently bind to those receptors. Along the way, that virus would pick up random genetic mutations that pop up but dont do anything noticeable, said Nikolai Petrovsky, in the College of Medicine and Public Health at Flinders.

The result of these experiments is a virus that is highly virulent in humans but is sufficiently different that it no longer resembles the original bat virus, Petrovsky said in a statement from the Australian Media Center. Because the mutations are acquired randomly by selection, there is no signature of a human gene jockey, but this is clearly a virus still created by human intervention.

If that virus infected a staff member and that person then traveled to the nearby seafood market, the virus could have spread from there, he said. Or, he added, an inappropriate disposal of waste from the facility could have infected humans directly or from a susceptible intermediary, such as a stray cat.

Though we may never get a definitive answer, at least in the near-term, some say it doesnt matter.

No matter the origin, evolution in nature and spillover to humans, accidental release from a lab, or deliberate release or genetic manipulation of a pathogen in the lab the way you develop countermeasures is the same, Keusch told Live Science. Since one can never say 100% for anything, I think we always need to be aware of all possibilities in order to contravene. But the response to develop what is needed to respond, control and eliminate the outbreak remains the same.

Live Science senior writer Rachael Rettner contributed to this report.

Originally published onLive Science.

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Wuhan lab says there's no way coronavirus originated there: Here's the science - Home - WSFX

Mutations present in our DNA from birth can cause us to die at a younger age.

By Amanda HeidtApr. 24, 2020 , 12:40 PM

Scientists have discovered a handful of ultrarare mutations present in our cells from birth that likely shave years off a persons life. Each of these DNA variants, most likely inherited from our parents, can reduce life span by as much as 6 months, the researchers estimate. And different combinations can dictate how long people live before developing age-related diseases such as cancer, diabetes, and dementia.

A persons genes dont set a specific natural life spandiet and many other factors play large roles, toobut studies have shown that DNA variants can influence the aging process. Biologists chalk up less than one-third of that influence to the genes we inherit. The source of other age-influencing DNA variation is environmental: Sun damage, chemical exposure, and other insults that create thousands of random mutations. Each cells collection of these environmental mutations differs, and most dont greatly impact a persons life span.

Hunting for these rare mutations, which are found in less than one in every 10,000 people, required a group effort. Harvard University geneticist Vadim Gladyshev, a senior co-author in the new study, partnered with academic colleagues and a biotech company called Gero LLC to scour the UK Biobank, a public database containing the genotypes of about 500,000 volunteers.

Using more than 40,000 of these genotypes, the team looked for correlations between small changes in DNA and health conditions, a so-called genomewide association study. Specifically, the variants they were targeting knock out genes entirely, depriving all the cells in the body of certain proteins.

On average, each person is born with six ultrarare variants that can decrease life span and health span, the amount of time people live before developing serious diseases, the team reports this month in eLife. The more mutations, the more likely a person was to develop an age-related illness at a younger age or die. The exact combination matters, Gladyshev says, but in general, each mutation decreases life span by 6 months and health span by 2 months.

The results build on what is already known about aging: Family genes matter. But rather than studying the common mutations found in especially long-lived people, researchers can now target rarer variants present in everyone. Gladyshev hopes this information can be used in clinical trials to categorize participants by their mutations in addition to things like gender and actual age.

He admits the findings are potentially controversial, as they minimize the perceived contribution to aging of environmental somatic mutations acquired throughout life. Somatic mutations live in a larger universe of age-related changes influenced by lifestyle, he says, adding that changes to hormone and gene expression also come with age. They [all] contribute to the aging process, but on their own they do not cause it.

Jan Vijg, a geneticist at the Albert Einstein College of Medicine who studies the role of somatic mutations in aging, agrees, though he adds that somatic mutations can still cause diseases such as skin cancer that decrease life span.

Alexis Battle, a biomedical engineer at the Johns Hopkins University School of Medicine, points to an important caveat, however: The new research only looked at the exome, the 1% of the genome that actively builds the proteins that direct our cells. The rest is largely a black box, although growing evidence shows it can affect gene expression. Both Battle and Vijg agree that this DNA could be even more important in aging than the regions targeted by Gladyshev and his colleagues.

Going forward, Gladyshev would like to repeat his analysis on DNA from centenarians: those that live to be older than 100. Most of the previous research focused on what these people have that makes them long-lived, he says. But [we want to look at] the oppositeits what they dont have.

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Rare 'killer' mutations present at birth could be taking years off your life - Science Magazine

A study by researchers at the Johns Hopkins Kimmel Cancer Center and six other medical centers, inlcuding the University of Iowa and Duke University, have identified a set of molecular markers linked to a chemical process called methylation that may help predict the risk of cancer recurrence within five years for patients with triple-negative breast cancers (TNBC).[1]

Triple-negative breast cancer (TNBC), which lacks expression of the estrogen (ER), progesterone (PR), and HER2 receptors, is an aggressive type of breast cancer, accounting for up to 20% of all breast cancers with poorer survival rates than other types of breast cancer. [2] TNBC is diagnosed more frequently in younger and premenopausal women and is highly prevalent in African American and Hispanic women.[3]

Because of the absence of receptors seen in other forms of breast cancer, TNBC is unresponsive to the targeted hormonal and anti-HER2 therapies used to treat patients diagnosed with other breast cancers. Furthermore, one of the features of TNBC is that the most widely used gene expression profiling tests, including 21-gene Oncotype DX, the 70-gene Mammaprint, or the PAM50, have no clinical utility in patients with TNBC.

Overall, about one-quarter of these cancers recur within five years of localized treatment with surgery or radiation. Physicians currently lack accurate tools to identify which patients are at greatest risk of recurrence.

HypothesisIn the study, the researchers were able to confirm their hypothesis that higher levels of methylation* would be associated with earlier recurrence and worse outcomes for patients.

The finding did, however, not distinguish specific levels of methylation or specific methylation markers that could be used to personalize patient treatment, noted Christopher B. Umbricht, M.D., Ph.D., associate professor of surgery, oncology, and pathology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center and the studys author.

In an article published in the January 31, 2020, issue of the journal npg Breast Cancer, Umbricht noted that their results may support physicians decisions to manage patients with less aggressive disease more conservatively and trigger earlier treatment for those with more aggressive disease.

StudyUmbricht and his colleagues examined breast cancer tissue from 110 triple-negative breast cancer (TNBC) patients from archival tissue repositories to look for the biological footprints of DNA methylation, an epigenetic process that can chemically silence genes that suppress tumors and has been well-documented across many types of cancer. The researchers observed that high methylation was associated with shorter recurrence-free interval

Based on these results they identified a set of such molecular markers in which higher levels of methylation were associated with a greater risk of a five-year recurrence of TNBC, confirming that their hypermethylation signatures identified increased recurrence risk independent of whether patients received chemotherapy.

Notes* Methylation refers to the addition of a methyl group (three hydrogen atoms bound to a carbon atom) to a DNA molecule.** Epigenetic process refers to the process where chemical compounds are added to genes to regulate their activity

Reference[1] Fackler MJ, Cho S, Cope L, et al. DNA methylation markers predict recurrence-free interval in triple-negative breast cancer. NPJ Breast Cancer. 2020;6:3. Published 2020 Jan 31. doi:10.1038/s41523-020-0145-3 [Article][2] Li CH, Karantza V, Aktan G, et al. Current treatment landscape for patients with locally recurrent inoperable or metastatic triple-negative breast cancer: a systematic literature review. Breast Cancer Res. 2019 Dec 16;21(1):143.[3] Wahba HA, El-Hadaad HA. Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med. 2015 Jun;12(2):106-16.

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Risk of Recurrence of Triple-Negative Breast Cancer May be Predicted by Molecular Biomarkers - OncoZine

Nearly a decade ago, researchers at UT Southwestern Medical Center discovered that when mouse hearts were damaged in the first seven days of life, they would regenerate. They reasoned that if they could find a way to recreate that regenerative ability later in life, it might provide a new way to treat heart damage.

Now, that same team has discovered that a protein called calcineurin plays a key role in blocking the ability of heart muscle to regenerate after the first week of life. The discovery could be used to develop treatments that reverse this process, in essence returning the heart to its developmental stage, they reported in the journal Nature.

The discovery builds on previous work at UT Southwestern that focused on the protein Meis1, a transcription factor that prevents heart cells from dividing. When the researchers deleted the gene in mice that makes that protein, their cardiomyocytes continued to divide after the first week of life. But the effect was transient.

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Then the researchers discovered that another protein called Hoxb13 was also key, because it shuttles Meis1 into the cell nucleus. So they deleted the genes for both Meis1 and Hoxb13 in adult mice to see what would happen after a heart attack.

It worked. The ability of the animals hearts to pump blood quickly returned to near-normal levels, they said. Even though the mice were adults, their hearts looked much like they would in animals that were still developing.

After a series of further experiments, the UT Southwestern scientists discovered that calcineurin regulates both Hoxb13 and Meis1. Inhibiting calcineurin prolongs the window of cardiomyocyte proliferation, they wrote in the study.

The idea of treating heart damage by turning back the clock isnt new. In fact, several research teams have tried using stem cells to repair damaged heart tissue. But those efforts have been disappointing so far.

Last year, a team from the Cincinnati Children's Hospital Medical Center tracked stem cells injected into the hearts of mice and concluded that it was not the cells themselves, but rather their ability to activate macrophage cells from the immune system that promoted healing. That led the researchers to suggest that efforts to regenerate the heart focus less on stem cells and more on other processes in the body that might promote healing.

The discovery of calcineurins role in regulating the regeneration of the heart is notable due to the fact that there are already drugs on the market that target the protein. Thats because calcineurin plays a role in a variety of diseases, including rheumatoid arthritis and diabetes. Testing these drugs, either individually or in combination, and developing new medicines that target calcineurin directly could offer new strategies for repairing hearts damaged by heart attacks, high blood pressure, viruses and more, suggested co-author Hesham Sadek, M.D., Ph.D., a professor of internal medicine, molecular biology and biophysics at UT Southwestern.

"By building up the story of the fundamental mechanisms of heart cell division and what blocks it, Sadek said in a statement, we are now significantly closer to being able to harness these pathways to save lives.

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CRISPR corrects genetic defect so cells can normalize blood sugar

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome.

Using induced pluripotent stem cells produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used the gene-editing tool CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured the unrelenting diabetes in those mice.

The findings, from researchers at Washington University School of Medicine in St. Louis, suggest the CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation, and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

The study is published online April 22 in the journal Science Translational Medicine.

Patients with Wolfram syndrome develop diabetes during childhood or adolescence and quickly require insulin-replacement therapy, requiring insulin injections multiple times each day. Most go on to develop problems with vision and balance, as well as other issues, and in many patients, the syndrome contributes to an early death.

This is the first time CRISPR has been used to fix a patients diabetes-causing genetic defect and successfully reverse diabetes, said co-senior investigator Jeffrey R. Millman, PhD, an assistant professor of medicine and of biomedical engineering at Washington University. For this study, we used cells from a patient with Wolfram syndrome because, conceptually, we knew it would be easier to correct a defect caused by a single gene. But we see this as a stepping stone toward applying gene therapy to a broader population of patients with diabetes.

Wolfram syndrome is caused by mutations to a single gene, providing the researchers an opportunity to determine whether combining stem cell technology with CRISPR to correct the genetic error also might correct the diabetes caused by the mutation.

A few years ago, Millman and his colleagues discovered how to convert human stem cells into pancreatic beta cells. When such cells encounter blood sugar, they secrete insulin. Recently, those same researchers developed a new technique to more efficiently convert human stem cells into beta cells that are considerably better at controlling blood sugar.

In this study, they took the additional steps of deriving these cells from patients and using the CRISPR-Cas9 gene-editing tool on those cells to correct a mutation to the gene that causes Wolfram syndrome (WFS1). Then, the researchers compared the gene-edited cells to insulin-secreting beta cells from the same batch of stem cells that had not undergone editing with CRISPR.

In the test tube and in mice with a severe form of diabetes, the newly grown beta cells that were edited with CRISPR more efficiently secreted insulin in response to glucose. Diabetes disappeared quickly in mice with the CRISPR-edited cells implanted beneath the skin, and the animals blood sugar levels remained in normal range for the entire six months they were monitored. Animals receiving unedited beta cells remained diabetic. Their newly implanted beta cells could produce insulin, just not enough to reverse their diabetes.

We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation, said co-senior investigator Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine and a professor of pathology and immunology. Its a proof of concept demonstrating that correcting gene defects that cause or contribute to diabetes in this case, in the Wolfram syndrome gene we can make beta cells that more effectively control blood sugar. Its also possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.

In the future, using CRISPR to correct certain mutations in beta cells may help patients whose diabetes is the result of multiple genetic and environmental factors, such as type 1, caused by an autoimmune process that destroys beta cells, and type 2, which is closely linked to obesity and a systemic process called insulin resistance.

Were excited about the fact that we were able to combine these two technologies growing beta cells from induced pluripotent stem cells and using CRISPR to correct genetic defects, Millman said. In fact, we found that corrected beta cells were indistinguishable from beta cells made from the stem cells of healthy people without diabetes.

Moving forward, the process of making beta cells from stem cells should get easier, the researchers said. For example, the scientists have developed less intrusive methods, making induced pluripotent stem cells from blood and they are working on developing stem cells from urine samples.

In the future, Urano said, we may be able to take a few milliliters of urine from a patient, make stem cells that we then can grow into beta cells, correct mutations in those cells with CRISPR, transplant them back into the patient, and cure their diabetes in our clinic. Genetic testing in patients with diabetes will guide us to identify genes that should be corrected, which will lead to a personalized regenerative gene therapy.

Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, Millman JR. Gene-edited human stem cell-derived cells from a patient with monogenic diabetes reverse pre-existing diabetes in mice. Science Translational Medicine, published online April 22, 2020.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of General Medical Sciences, the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Grant numbers R01 DK114233, DK112921, TR002065, TR002345, T32 DK108742, R25 GM103757, T32 DK007120, P30 DK020579, P30 CA91842, UL1 TR000448 and UL1 TR002345. Additional assistance was provided by the Washington University Genome Engineering and iPSC Center, the Washington University Diabetes Center, and the Washington University Institute of Clnical and Translational Science, with additional funding from the JDRF, the Washington University Center of Regenerative Medicine, startup funds from the Washington University School of Medicine Department of Medicine, the Unravel Wolfram Syndrome Fund, Silberman Fund, Stowe Fund, Ellie White Foundation for Rare Genetic Disorders, Eye Hope Foundation, Snow Foundation, Feiock Fund, Childrens Discovery Institute, Manpei Suzuki Diabetes Foundation, and a JSPS Overseas Research Fellowship.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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