Monthly Archives: February 2017

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Small sheets of healthy skin are being grown from scratch at a Stanford University lab, proof that gene therapy can help heal a rare disease that causes great human suffering.

The precious skin represents growing hope for patients who suffer from the incurable blistering disease epidermolysis bullosa and acceleration of the once-beleaguered field of gene therapy, which strives to cure disease by inserting missing genes into sick cells.

It is pink and healthy. Its tougher. It doesnt blister, said patient and research volunteer Monique Roeder, 33, of Cedar City, Utah, who has received grafts of corrected skin cells, each about the size of an iPhone 5, to cover wounds on her arms.

More than 10,000 human diseases are caused by a single gene defect, and epidermolysis bullosa is among the most devastating. Patients lack a critical protein that binds the layers of skin together. Without this protein, the skin tears apart, causing severe pain, infection, disfigurement and in many cases, early death from an aggressive form of skin cancer.

The corrected skin is part of a pipeline of potential gene therapies at Stanfords new Center for Definitive and Curative Medicine, announced last week.

The center, a new joint initiative of Stanford Healthcare, Stanford Childrens Health, and the Stanford School of Medicine, is designed to accelerate cellular therapies at the universitys state-of-the-art manufacturing facility on Palo Altos California Avenue. Simultaneously, itisaiming to bring cures to patients faster than before and boost the financial value of Stanfords discoveries before theyre licensed out to biotech companies.

With trials such as these, we are entering a new era in medicine, said Dr. Lloyd B. Minor, dean of the Stanford University School of Medicine.

Gene therapy was dealt a major setback in 1999 when Jesse Gelsinger, an Arizona teenager with a genetic liver disease, had a fatal reaction to the virus that scientists had used to insert a corrective gene.

But current trials are safer, more precise and build on better basic understanding. Stanford is also using gene therapy to target other diseases, such as sickle cell anemia and beta thalassemia,a blood disorder that reduces the production of hemoglobin.

There are several diseases that are miserable and worthy of gene therapy approaches, said associate professor of dermatology Dr. Jean Tang, who co-led the trial with Dr. Peter Marinkovich. But epidermolysis bullosa, she said, is one of the worst of the worst.

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It took nearly 20 years for Stanford researchers to bring this gene therapy to Roeder and her fellow patients.

It is very satisfying to be able to finally give patients something that can help them, said Marinkovich.In some cases, wounds that had not healed for five years were successfully healed with the gene therapy.

Before, he noted, there was only limited amounts of what you can do for them. We can treat their wounds and give them sophisticated Band-Aids. But after you give them all that stuff, you still see the skin falling apart, Marinkovich said. This makes you feel like youre making a difference in the world.

Roeder seemed healthy at birth. But when her family celebrated her arrival by imprinting her tiny feet on a keepsake birth certificate, she blistered. They encouraged her to lead a normal childhood, riding bicycles and gentle horses. Shes happily married. But shes grown cautious, focusing on photography, writing a blog and enjoying her pets.

Scarring has caused her hands and feet digits to become mittened or webbed. Due to pain and risk of injury, she uses a wheelchair rather than walking long distances.

Every movement has to be planned out in my head so I dont upset my skin somehow, she said. Wound care can take three to six hours a day.

She heard about the Stanford research shortly after losing her best friend, who also had epidermolysis bullosa, to skin cancer, a common consequence of the disease. Roeder thought: Why dont you try? She didnt get the chance.

The team of Stanford experts harvested a small sample of skin cells, about the size of a pencil eraser, from her back. They put her cells in warm broth in a petri dish, where they thrived.

To this broth they added a special virus, carrying the missing gene. Once infected, the cells began producing normal collagen.

They coaxed these genetically corrected cells to form sheets of skin. The sheets were then surgically grafted onto a patients chronic or new wounds in six locations. The team reported their initial results in Novembers Journal of the American Medical Association.

Historically, medical treatment has had limited options: excising a sick organ or giving medicine, said Dr. Anthony E. Oro of Stanfords Institute for Stem Cell Biology and Regenerative Medicine. When those two arent possible, theres only symptom relief.

But the deciphering of the human genome, and new tools in gene repair, have changed the therapeutic landscape.

Now that we know the genetic basis of disease, we can use the confluence of stem cell biology, genome editing and tissue engineering to develop therapies, Oro said.

Its not practical to wrap the entire body of a patient with epidermolysis bullosa in vast sheets of new skin, like a mummy, Oro said.

But now that the team has proved that gene therapy works, they can try related approaches, such as using gene-editing tools directly on the patients skin, or applying corrected cells like a spray-on tan.

A cure doesnt take one step, said Tang. It takes many steps towards disease modification, and this is the first big one. Were always looking for something better.

Read more here:
Stanford team is growing healthy skin for ill patients - The Mercury News

February 7, 2017 A cartoon shows gene editing through engineered CRISPR/Cas9En delivery in the Rotello lab at UMass Amherst. The researchers have overcome an obstacle in the technology by designing a delivery system using nanoparticles to assist CRISPR/Cas9 across the cell membrane and into the nucleus while avoiding entrapment by cellular machinery. Credit: UMass Amherst

More and more scientists are using the powerful new gene-editing tool known as CRISPR/Cas9, a technology isolated from bacteria, that holds promise for new treatment of such genetic diseases as cystic fibrosis, muscular dystrophy and hemophilia. But to work well, the new gene-clipping tool must be delivered safely across the cell membrane and into its nucleus, a difficult process that can trigger the cell's defenses and "trap" CRISPR/Cas9, greatly reducing its treatment potential.

Now, researchers in nanochemistry expert Vincent Rotello's laboratory at the University of Massachusetts Amherst have designed a delivery system using nanoparticles to assist CRISPR/Cas9 across the membrane and into the cell nucleus while avoiding entrapment by cellular machinery. Details appear in a recent issue of the journal ACS Nano.

The lab's experiment leader, Rubul Mout, says, "CRISPR has two components: a scissor-like protein called Cas9, and an RNA molecule called sgRNA that guides Cas9 to its target gene. Once the Cas9-sgRNA pair gets to the destination gene in the nucleus, it can interrogate its genetic mistakes and correct them with the help of the host cell's repair machinery."

He points out that since CRISPR's potential was first discovered in 2012, gene editing or genome engineering has quickly become an intense research topic in biology and medicine. The goal is to treat otherwise incurable genetic diseases by manipulating diseased genes. "However, to achieve this, biotech and pharmaceutical companies are constantly searching for more efficient CRISPR delivery methods," he adds.

The new delivery method Rotello, Mout and colleagues designed involves engineering the Cas9 protein, named Cas9En, and carrier nanoparticles. Rotello says, "By finely tuning the interactions between engineered Cas9En protein and nanoparticles, we were able to construct these delivery vectors. The vectors carrying the Cas9 protein and sgRNA come into contact with the cell membrane, fuse, and release the Cas9:sgRNA directly into the cell cytoplasm."

"Cas9 protein also has a nuclear guiding sequence that ushers the complex into the destination nucleus. The key is to tweak the Cas9 protein," he adds. "We have delivered this Cas9 protein and sgRNA pair into the cell nucleus without getting it trapped on its way. We have watched the delivery process live in real time using sophisticated microscopy."

Mout and colleagues say they can now deliver the Cas9 protein and sgRNA pair into about 90 percent of cells grown in a culture dish with an editing efficiency of about 30 percent. "Ninety percent cytosolic/nuclear delivery is a huge improvement compared to others methods," Mout points out.

The researchers believe that the Cas9En may also serve as a platform for delivery of a variety of other materials such as polymers, lipid nanoparticles or self-assembling peptides. Rotello says, "Now that we have achieved efficient gene editing in cultured cells, we are aiming to edit genes in pre-clinical animal models. We are also interested in gene editing for adoptive therapies, where a diseased cell is isolated from a patient, corrected by CRISPR in the lab, and delivered back to the patient."

Apart from gene editing, the new delivery method may have other uses. For example, another important issue in biology and medicine is tracking DNA and RNA inside cells. Recently, CRISPR has been used to aid in this research. Moumita Ray, another researcher in the Rotello lab, says, "Our method allows the precise monitoring of Cas9 protein movement inside a cell, opening new opportunities in genomic research."

Explore further: Watching gene editing at work to develop precision therapies

More information: Rubul Mout et al. Direct Cytosolic Delivery of CRISPR/Cas9-Ribonucleoprotein for Efficient Gene Editing, ACS Nano (2017). DOI: 10.1021/acsnano.6b07600

University of Wisconsin-Madison engineers have developed methods to observe gene editing in action, and they're putting those capabilities to work to improve genetic engineering techniques.

A study in The Journal of Cell Biology by scientists at the University of Massachusetts Medical School reveals important new details about the inner workings of the CRISPR-Cas9 machinery in live cells that may have implications ...

The ability to control gene expression in cells allows scientists to understand gene function and manipulate cell fate. Recently, scientists have developed a revolutionary gene-editing tool, called CRIPSR/Cas9, which employs ...

Researchers have discovered a way to program cells to inhibit CRISPR-Cas9 activity. "Anti-CRISPR" proteins had previously been isolated from viruses that infect bacteria, but now University of Toronto and University of Massachusetts ...

(Phys.org)A team of researchers with members from several institutions in Japan has developed a new way to edit genes that involves cutting just one strand of DNA rather than both of them, as is normal for CRISPR-Cas9. ...

Researchers from North Carolina State University and the University of North Carolina at Chapel Hill have for the first time created and used a nanoscale vehicle made of DNA to deliver a CRISPR-Cas9 gene-editing tool into ...

More and more scientists are using the powerful new gene-editing tool known as CRISPR/Cas9, a technology isolated from bacteria, that holds promise for new treatment of such genetic diseases as cystic fibrosis, muscular dystrophy ...

Inspired by the hair of blue tarantulas, researchers from The University of Akron lead a team that made a structural-colored material that shows consistent color from all viewing directions. This finding overturns the conventional ...

Using tiny snippets of DNA as "barcodes," researchers have developed a new technique for rapidly screening the ability of nanoparticles to selectively deliver therapeutic genes to specific organs of the body. The technique ...

How the natural defence force within our immune system attacks and destroys harmful invaders such as virus-infected and cancerous cells has been visualised in microscopic detail by scientists from UCL, Birkbeck, University ...

(Phys.org)In an effort to curb the adverse environmental impacts of paper production, researchers in a new study have developed a light-printable paperpaper that can be printed with UV light, erased by heating to 120 ...

Scientists used one of the world's most powerful electron microscopes to map the precise location and chemical type of 23,000 atoms in an extremely small particle made of iron and platinum.

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Overcoming hurdles in CRISPR gene editing to improve treatment - Phys.Org

Only half got BRCA screen, and more than half of those who didn't said doctors never recommended it

By Kathleen Doheny

HealthDay Reporter

TUESDAY, Feb. 7, 2017 (HealthDay News) -- Though testing for two genes that raise breast cancer risk has been around for decades, a new survey finds many high-risk women don't get the test, often because they aren't told to by their doctors.

Among women with the highest risk, about eight of 10 said they wanted testing for the BRCA1 and BRCA2 mutations. But, "only about half of them actually got the testing they should get," said study author Dr. Allison Kurian, from Stanford University's School of Medicine.

"Genetic cancer testing is not well matched to the medical needs of the patient, to a woman's risk of having a mutation," said Kurian, an associate professor of medicine and of health research and policy.

Why the gap?

About 56 percent of the high-risk women who were not tested said their doctors did not recommend it, the survey found.

In addition to the test itself, genetic counseling can help patients decide whether to seek testing or help them understand test results. But only about 40 percent of all high-risk women, and 60 percent of high-risk women who were tested, said they got such counseling, Kurian's team found.

In the survey, more than 2,500 women with breast cancer were questioned two months after surgery. The patients were asked if they had wanted genetic testing and, if so, whether they had received it. The women ranged in risk, with 31 percent having a high risk of carrying the BRCA mutations that raise both breast and ovarian cancer risk.

Asian Americans and older women were particularly likely to not have been tested, the survey found.

"I think it's very concerning," Kurian said of the findings. She noted that the survey was limited because it was based only on women's responses and recollections. For instance, doctors might have mentioned genetic testing and women might have forgotten that.

Genetic testing, when warranted, can help determine a woman's risk of future cancer and sometimes guide the best type of treatment, Kurian said. A woman can also alert close relatives, such as sisters and daughters, about positive results, in case they want to get tested.

Guidelines from organizations such as the National Comprehensive Cancer Network and the American College of Obstetricians and Gynecologists recommend genetic testing based on risk. An example of someone who should consider it, Kurian said, would be a woman who had breast cancer before age 50 and has a first-degree relative with the disease.

"It used to be this testing was very expensive, costing around $4,000," Kurian said. Then the U.S. Supreme Court ruled in 2013 that genes couldn't be patented, which opened the way for other companies to offer the testing. If not covered by insurance, women can now get the tests for about $250 to $500.

That change was reflected in the findings: Less than 14 percent of the women cited expense as a barrier to testing.

According to Dr. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society, "The study hits home. It points out a fundamental problem in what we do and how we do it."

For genetic testing, he said, the science is there, the capability is there, but the implementation is lacking.

However, he cited some limitations with the survey. As Kurian said, the testing information was self-reported, so it may not have been entirely accurate.

Also, the timing of the survey -- from July 2013 to September 2014 -- could have affected the results, Lichtenfeld added.

"Genetic testing was available, but only through a single company, through June of 2013," he said. Other labs may still have been gearing up when the survey ended, so testing prices may not have dropped at that point, Lichtenfeld said.

The geographic area surveyed was also limited, he said, including just Georgia and California.

And while the testing has become less expensive, insurance coverage isn't universal, according to Lichtenfeld. Some plans won't cover testing until a woman is already diagnosed with cancer or they may set additional criteria, such as having a cancer diagnosis and a relative with cancer.

Health professionals need to do a better job of checking and updating family history and understanding what the genetic risk factors for breast cancer might be, Lichtenfeld said. And they need to talk more about genetic testing to patients, he added.

Kurian also said that more genetic counselors are needed.

The study was published Feb. 7 in the Journal of the American Medical Association, and was funded by the U.S. National Institutes of Health.

WebMD News from HealthDay

SOURCES: Allison Kurian, M.D., M.Sc., associate professor, medicine and of health research and policy, Stanford University School of Medicine, Stanford, Calif.; Leonard Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society, Atlanta; Feb. 7, 2017, Journal of the American Medical Association

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High-Risk Women and Breast Cancer Gene Test - WebMD

For some medical students, changing the world can't wait until after graduation. That's the case for Richard Morgan and Edgar Corona, students at UCLA'sDavid Geffen School of Medicine who started working on thismission even before adding M.D. to their names.

A fourth-year medical student, Morgan is conducting research to develop a new gene therapy vector for the treatment of sickle cell disease.This approach uses a patients own blood-producing stem cells to create a lifelong supply of healthy red blood cells.My goal is to be a world-class hematologist, capable of transforming the health of patients afflicted with devastating blood disorders, Morgan said.

Hes not stopping there. Morgan is also committed to fighting health care disparities in underserved communities, where chronic conditions such as sickle cell disease take a disproportionate toll.

Patients in underserved communities diagnosed with chronic illness often experience obstacles in obtaining treatment, adding to their suffering, said Morgan. To reduce these disparities, hehas helped organize health fairs in Central Los Angeles and Watts through programs at Charles R. Drew University of Medicine and Science.He has also served as a student mentor to minority high school students.

Mentorship is important because we need more physicians who understand issues that people from underserved communities face when obtaining care, he said.

Reed Hutchinson/UCLA

Medical student Edgar Corona advises a student.

Edgar Corona, a third-year medical student in the UCLA/PRIME dual-degree program, shares Morgans passion for working with underserved communities. All patients deserve to be treated with kindness and respect thats why Im committed to a career in addressing health care disparities by implementing evidence-based programs and practices, he said.

Corona is already making strong headway in that direction. As a UCLA undergraduate working with the Latino Student Health Project, he and his four student co-directors organized trips for UCLA resident physicians to provide medical care to medically underserved communities in Mexico. As a medical student working with the UCLA Blum Center on Poverty and Health in Latin America, Corona conducted population-based research in Morelos, Mexico, on the effectiveness of a cervical cancer prevention program. Whats more, as vice president of community affairs for the Latino Medical Student Association's west regional group, he wrote a proposal that resulted in a five-year, $300,000 grant from AltaMed, funds that will be used for scholarships and leadership training.

Morgan'sand Coronas efforts to make the world a better place have not gone unnoticed.

Morgan was awarded the National Medical Fellowships Franklin C. McLean Awardin recognition of his outstanding academic achievement, leadership and community service. Corona received the Herbert W. Nickens Medical Student Scholarship from the Association of American Medical Collegesfor demonstrating leadership in his efforts to eliminate inequities in both medical education and health care in minority communities.

Having both grown up in urban areas, Morgan and Corona experienced the very inequities theyre now fighting against. In fact, both were inspired to pursue medicine after seeing the difficulties their mothers faced when they tried to obtain quality health care.

Morgans mother battled diabetes with little access to free or affordable health care. Morgan was moved by the many devoted physicians who were willing to help her. Their compassion and their conviction that health care is a universal right inspired me to pursue this career path, he said.

Similarly, Corona watched his mother struggle after she broke her foot and tried to navigate the public health care system, encountering long commutes and wait times, and a scarcity of doctors who understood Spanish. Ironically, my mothers difficulties became a catalyst for me to pursue a career in health care to improve the health systems that serve vulnerable communities, he said.

Morgan and Corona are also grateful for their mentors. Morgan met his mentor, Dr. Donald Kohn,through the UCLA Medical Scientist Training Program. Dr. Kohn is a world-class expert in developing gene therapy strategies for the treatment of monogenic disorders of the bone marrow, said Morgan. Im honored to work with him.

Coronas mentor, Dr. Efrain Talamantes, inspired him to co-found Alliance in Mentorship, a nonprofit organization dedicated to providing innovative mentorship opportunities to aspiring health professionals. When Dr. Talamantes reached out to me about working alongside him with this idea, he and I just took off with it, said Corona. And today my involvement in developing the organization is the work Im most proud of. The alliancehas generated Mimentor.org, a great online resource for students looking for mentorship as they pursue a career in health care.

The dedication, passion and hard work of Morgan and Corona exemplify the commitment that students at the David Geffen School of Medicine at UCLA have to the larger community.

Im so grateful for the McLean Award, and I hope that in the future, I will impress the medical community in a significant way, said Morgan.

The Nickens Scholarship shows that medical schools care about decreasing health and education inequities, and it serves as another reminder that the work that I and students like me are doing is important, said Corona.

Read the original here:
Two medical students tackle the task of changing the world - UCLA Newsroom

February 7, 2017 Credit:

Bacteria are not the sole cause of caries; tooth resistance also plays an instrumental role. Researchers from the University of Zurich demonstrate that mutated genes lead to defects in the tooth enamel and can therefore encourage the development of caries.

Why do some people develop caries even though they always brush their teeth carefully while others are less stringent regarding dental hygiene yet do not have any holes? Ultimately, both have bacteria on the surface of their teeth which can attack the enamel. Enamel forms via the mineralization of specific enamel proteins. If the outer layer of the teeth is defective, tooth decay can strike.

Researchers from the University of Zurich have now pinpointed a gene complex for the first time that is responsible for the formation of tooth enamel. Two teams from the Centre of Dental Medicine and the Institute of Molecular Life Sciences used mice with varying mutations of the enamel proteins involved in the so-called Wnt signaling pathway. Thanks to this transmission route, human and animal cells respond to external signals and specifically activate selected genes in the cell nucleus. The signaling pathway is essential for embryonal development and also plays a pivotal role in the development of cancer or physical malformations.

Mutations in proteins trigger defective tooth enamel

"All mice with mutations in these proteins exhibit teeth with enamel defects," explains Pierfrancesco Pagella, one of the study's two first authors. "Therefore, we demonstrated that there is a direct link between mutations in the genetic blueprints for these proteins and the development of tooth enamel defects." This genetic discovery goes a long way towards improving our understanding of the production of tooth enamel.

The team of researchers was the first in the world to use modern genetic, molecular and biochemical methods to study tooth enamel defects in detail. "We discovered that three particular proteins involved in the Wnt signaling pathway aren't just involved in the development of severe illnesses, but also in the qualitative refinement of highly developed tissue," says co-first author Claudio Cant from the molecular biologist research group lead by Prof. Konrad Basler. "If the signal transmission isn't working properly, the structure of the tooth enamel can change."

Increased risk of caries with defective tooth enamel

The hardness and composition of the tooth enamel can affect the progression of caries. "We revealed that tooth decay isn't just linked to bacteria, but also the tooth's resistance," says Thimios Mitsiadis, Professor of Oral Biology at the Center of Dental Medicine. Bacteria and their toxic products can easily penetrate enamel with a less stable structure, which leads to carious lesions, even if oral hygiene is maintained.

Understanding the molecular-biological connections of tooth enamel development and the impact of mutations that lead to enamel defects opens up new possibilities for the prevention of caries. "New products that hinder the progress of tooth caries in the event of defective tooth enamel will enable us to improve the dental health of patients considerably," adds Mitsiadis.

Explore further: Hair proteins are important in tooth enamel structure

More information: C. Cant, P. Pagella, T. D. Shajiei, D. Zimmerli, T. Valenta, G. Hausmann, K. Basler and T. A. Mitsiadis. A cytoplasmic role of Wnt--catenin transcriptional cofactors in tooth enamel formation. Science Signaling. February 7, 2017. DOI: 10.1126/scisignal.aah4598

Tooth decay is one of the most common chronic diseases worldwide. While oral hygiene and dietary choices promote tooth decay, genetics are also a factor in cavity formation.

Today at the 93rd General Session and Exhibition of the International Association for Dental Research, researcher Olivier Duverger, National Institutes of Health-National Institute of Neurological Disorders and Stroke, Bethesda, ...

A new study has revealed that children's teeth are protected from damage during chewing by variation in enamel thickness along the tooth row.

Today, the International and American Associations for Dental Research (IADR/AADR) published an innovative developmental biology study by lead researcher Bernhard Ganss, University of Toronto, ON, Canada, that relates amelotin ...

Bacteria are not the sole cause of caries; tooth resistance also plays an instrumental role. Researchers from the University of Zurich demonstrate that mutated genes lead to defects in the tooth enamel and can therefore encourage ...

A new method of stimulating the renewal of living stem cells in tooth pulp using an Alzheimer's drug has been discovered by a team of researchers at King's College London.

A world-first vaccine developed by Melbourne scientists, which could eliminate or at least reduce the need for surgery and antibiotics for severe gum disease, has been validated by research published this weekend in a leading ...

Being struck by Cupid's arrow can be good for your teeth.

Researchers have developed computer simulations showing how lasers attack oral bacterial colonies, suggesting that benefits of using lasers in oral debridement include killing bacteria and promoting better dental health.

For decades, research has suggested a link between oral health and inflammatory diseases affecting the entire bodyin particular, heart attacks and strokes.

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Genetic defects in tooth enamel conducive to development of caries - Medical Xpress