chairoij/ShutterStockImagine having your spleen removed, undergoing a double hip replacement, and receiving monthly blood transfusions to prevent severe pain attacks, all by the age of 13. That was the life of a teenager in France with sickle cell disease (SCD) until October 2014, when he received experimental gene therapy as part of a clinical study. Now, hes completely off all medications and his SCD is essentially gone, making him the hopeful poster child for the worlds first effective sickle cell disease therapy. (Dont these medical miracles that doctors cant explain.)

Standard treatments were not able to control his SCD symptoms [but] since receiving the stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions, said study author Marina Cavazzana, MD, PhD, of Necker Hospital in Paris, France, where the trial was conducted, in a news release.

SCD is a inherited blood disorder where sufferers have sickle hemoglobin, an abnormal form of the oxygen-carrying protein which changes the shape of red blood cells (from a flexible disc shape to a rigid crescent one), making it hard for them to pass through blood vessels and often causing blockages that slow or stop the flow of oxygen-rich blood to nearby tissues, causing sudden and severe pain. Sickled red blood cells also die after 10 to 20 days, compared to normal ones which can live up to 120; this can cause the body to have trouble keeping up with red blood cell production, leading to anemia. A stem-cell transplant is currently the only curative option for patients, but fewer than 18 percent of patients are able to find a matching donor.

That is until now. The 13-year-old boy (known as Patient 1204) had bone marrow extracted, which was then genetically altered with the drug LentiGlobin BB305 so that his body made normal, healthy red blood cells instead of the sickle cells it was creating before. After just six months, the proportions of sickled red cells in his blood were significantly lower than those in untreated SCD patients. Now more than 15 months since the treatment, his body is still producing normal red blood cells and he hasnt experience any SCD-related episodes or hospitalizations, according to the study published in the New England Journal of Medicine.

Ive worked in gene therapy for a long time and we make small steps and know theres years more work. But here you have someone who has received gene therapy and has complete clinical remissionthats a huge step forward, Deborah Gill, PhD, of the gene medicine research group at the University of Oxford in England told BBC.

Scientists plan to test the drug on other sickle cell disease patients to see if the results are replicated.

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Teen's Sickle Cell Disease 'Reversed' with Groundbreaking Therapy - Reader's Digest

Mast cells, components of the immune system, are responsible for alleriges and asthma, conditions that debilitate millions. Yet relatively few scientists study them.

Hydar Ali of the University of Pennsylvania is a member of the select group of researchers for whom mast cells are a focus. A professor in the Department of Pathology and director of faculty advancement and diversity in Penns School of Dental Medicine, Ali has spent his career discerning the cells unique qualities and honing in on strategies to modulate their activity to improve health.

Obviously Im biased, but I do think that our findings are critically important, Ali said. These cells are relatively poorly understood, and yet weve been able to identify some of the most sought-after molecular targets to affect diseases like allergies and asthma that have the potential to kill.

Mast cells are part of the immune system and reside in tissues rather than in the blood stream. They are important for protecting the body from pathogens and contribute to wound healing but are most notorious for their involvement in inflammatory and allergic conditions. They are rich in histamine which is released when mast cells are activated and can lead to the quintessential signs of an allergic reaction: hives, itching and even anaphylaxis.

No living human has ever been shown to lack mast cells, and mutant mice that lack them are unable to fight microbial infection, said Ali, so its pretty clear that mast cells are there to protect us from infection. But the other side of the coin is that people who have too many mast cells can develop skin rashes, itch, nausea, vomiting, diarrhea and abdominal pain.

Because mast cells are present only in low numbers and cannot be extracted from the tissue, they are considered difficult to work with, and thus the pool of researchers who do so is limited.

Despite these hurdles, Ali started working with mast cells while pursuing his doctorate at University College London. His dissertation examined the diversity of mast cell types.

I looked at mast cells from different tissues and found tremendous heterogeneity, he said. So, for example, if you took a mast cell from the gut, that cell is different from one in the skin. Theres also variability when you go to different species, so there are major differences between mouse mast cells, rat mast cells and human mast cells.

These differences make translational work, moving from animal models to human treatments, a challenge, as Ali and many of his colleauges in the field have discovered.

After earning his Ph.D., Ali moved into a postdoctoral position at the National Institutes of Health, where a handful of labs focused on mast cells. He recalls headline-making news when scientists in a neighboring lab cloned the gene for the IgE receptor. This receptor binds IgE antibodies and triggers a signaling pathway associated with allergic diseases, eczema and other condtions.

I remember The New York Times said that a therapy for asthma was on the way, Ali said. You read so many things like this and they never come, but this was different.

Indeed, by the 2000s an asthma drug came on the market to target this receptor

Ali saw that the field was ripe for discovery. Wanting to continue his rearch in academica, he took a position at Duke University, working with Ralph Snyderman, who was then chancellor of health affairs. Snydermans research portfolio primarily examined white blood cells other than mast cells, notably neutrophils and macrophages, but Ali helped discover that mast cells could be used as a model system to study properties of neutrophil receptors in a different context.

In 1998, Ali was ready to run his own lab. He had had the good fortune of being awarded grants, from the NIH, American Lung Association and American Heart Association, all to study G protein coupled receptors, which, like IgE receptors, are present in large numbers on mast cells.

At Duke, he had discovered that one of these G-protein coupled receptors, or GPCRs, was activated by a protein called C3a, part of the complement pathway that can often promote inflammation. High levels of C3a was also known to be associated with an increased risk of asthma in humans.

After coming to Penn, Ali serendipitously discovered the presence of a new GPCR, known as MRGPRX2, which is found only on mast cells and not other immune cells.

Pursuing this finding led Ali and colleagues to find that small proteins called antimicrobial peptides, which were believed to only kill microbes directly, could activate mast cells through MRGPRX2 to harness the protective function of mast cells to help clear the invading microbes.

Working with Penn Dentals Henry Daniell, a professor in the Department of Biochemistry,Ali showed that a couple of these antimicrobial peptides, manufactured through Daniells patented biopharmaceutical plant-production platform, were able to activate the mast cells through MRGPRX2, showcasing the positive role of mast cells in defending the body against pathogens.

I think this highlights the fact that mast cells are playing a role in host defense, said Ali.

On the other side of this fine line, mast cells involvement in pathogenic conditions such as asthma, Alis lab has been at the forefront in discoveries with the potential to translate to human therapies.

Earlier researchers had found that a key receptor involved in chronic asthma and anaphylaxis in mice did not function the same way in humans. Thus much energy that was poured into developing inhibitors of that receptor in mice ended up being fruitless in the pursuit of human therapies.

Yet, Ali and colleagues showed that, in humans, similar effects were elicited by signaling through MRGPRX2. While they had also shown that activating this receptor led to improved antimicrobial effects, in the context of allergic response, blocking this receptor could inhibit the harmful inflammatory effects.

Its two sides of the same coin, Ali said.

With a new set of grants, Alis lab is working with the Fox Chase Chemical Diversity Center to screen for small molecules that mimic known antimicrobial peptides in activating mast cells through the MRGPRX2 and operate with a similar dual function, direct killing and activating mast cells to help in fending off the attack. Theyre also looking for potential drugs that block this receptors activity to reduce the effects of allergic and chronic inflammatory conditions.

In addition, theyre using mouse models that use human version of molecular receptors to continue unraveling the mysteries of mast cells. One project is looking at the association between MRGPRX2 actviation and worsening asthma, while another is looking at the connection between chronic heart and lung diseases and genetic variations in mast cell receptors.

The goal is keeping the work relevant to humans.

With animal models, Ali said, if you think a gene is important, you knock it out, you over express it, you generate a ton of data and can publish it in a very high-impact journal. And when you submit a grant, it looks like youre a very productive investigator, you have impressive results in mice. But the question is, does it relate to humans?

In May, Ali will present his recent findings on the mysteries of controlling mast cells through MRGPRX2 in a keynote lecture at the European Mast Cell and Basophil Research Network International Meeting in Prague.

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Penn Dental Medicine Professor Unlocks the Mysteries of Mast Cells - Penn: Office of University Communications

The Regenerative Medicine Workshop at Hilton Head began its third decade with a long and diverse lineup of researchers who presented their latest work on a spacious range of topics, from DNA barcoded technology to strategies to reverse tissue degeneration in rotator cuff injuries.

In other words, the usual dizzying array of up-to-the-minute research from some of the worlds leading scientists and engineers.

But if there was a topical theme to last weeks 21st annual workshop (March 1-4), it was immunology.

The Hilton Head summit has always been a place where you can learn about the great, late breaking innovations in regenerative medicine, says Ned Waller, professor in the Emory University School of Medicine, and a researcher with the Petit Institute for Bioengineering and Bioscience at Georgia Tech. What striking this year is, half the talks are about immunology.

And that suits Waller just fine. He is director of the Division of Stem Cell Transplantation and Immunotherapy at the Winship Cancer Institute of Emory, where he also directs the Bone Marrow and Stem Cell Transplant Center. And his research presentation at Hilton Head was entitled, Another Arrow in the Anti-cancer Quiver: VIP Immunotherapy.

Waller also is one of three co-directors of the Regenerative Engineering and Medicine (REM) research center, a consortium of research institutes in Georgia: Emory, Georgia Tech, and the University of Georgia. REM is one of four organizing partners of the workshop, the others being the Stem Cell and Regenerative Medicine Center at the University of Wisconsin, the Mayo Clinics Center for Regenerative Medicine, and the McGowan Institute for Regenerative Medicine at the University of Pittsburgh.

Accordingly, faculty, post-doctoral, and student researchers from those institutions were well represented. But the workshop also drew researchers from across the spectrum and the planet. Among the speakers were Ronald Germain from the National Institutes of Health, and Molly Stevens from Imperial College in London. Rolando Gittens, who earned his Ph.D. in bioengineering at Georgia Tech in 2012 and is now a research scientist at the Institute for Scientific Research and High Technology Services of Panama.

There were also deep-dive presentations from researchers based at Duke, Harvard, Tufts, and Yale universities, among others, and Jeff Hubbell, the Nerem Lecturer from the University of Chicago (who delivered a talk on Biomolecular Engineering in Regenerative Medicine and Immunotherapies).

Steve Stice, as co-director of the REM from the University of Georgia (UGA), the newest member of the consortium, appreciated the geographic range of work that was presented.

One of the nice things this years is that UGA and other institutions are well represented, says Stice, professor and director of the Regenerative Bioscience Center at UGA and a Petit Institute researcher. So its not just Emory and Georgia Tech, its also Mayo, and Wisconsin, and Pittsburgh, and weve brought in speakers from all over. Its really grown and become a highly recommended event in the regenerative medicine community.

Trainees postdocs, grad students, and at least one undergraduate had a chance to present their work, also. First there was the rapid fire presentations (5 minutes) on Thursday afternoon, then a research poster competition that night, featuring 65 different projects on display.

The winning poster came from Daniel Hachim, a grad student at the University of Pittsburgh, whose project is entitled, Unveiling Macrophage Populations and Mechanisms Driving the Better Remodeling Outcomes Associated with Shifting Phenotype in the Host Response Against Biomaterials.

Cheryl San Emeterio, a Ph.D. student at Georgia Tech, has presented posters the last three years at this event, but this was her first rapid fire presentation.

I thought it was flattering and inspiring, to talk among so many distinguished scientists here, says San Emeterio, who does her research in the lab of Ed Botchwey, associate professor in the Wallace H. Coulter Department of Biomedical Engineering (a joint department of Emory and Georgia Tech).

Its great to get my work out there on this scale, and I hope that people are interested and want to discuss it further. And maybe we can form some sort of productive collaboration, adds San Emeterio, whose research is entitled, Age-dependent immune Dysregulation during Repair of Volumetric Muscle Injury.

Standing near her poster for most of the evening was Madeline Smerchansky, a Petit Undergraduate Scholar from Georgia Tech attending her first Hilton Head conference. She saw the opportunity as something of an investment.

This is practice for the future, says Smerchansky, a third-year student.

At least one researcher during the four-day workshop offered a glimpse into the future from a perspective that did not include biomolecular science or immunology. Aaron Levine offered his insights , but not the usual stuff based in biomolecular science or bioengineering. Aaron Levine, associate professor in the School of Public Policy at Georgia Tech and a Petit Institute researcher, delivered a presentation called, Regenerative Medicine in a Time of Policy Uncertainty.

We havent seen a lot of clear signals yet with how the policy environment is going to play out from the current presidential administration, says Levine, who focused his Friday morning talk on, among other things, potential policy drivers for regenerative medicine, such as the 21st Century Cures Act (will it be implemented by this administration, and if so, how much of it?), and the appointment of a commissioner for the Food and Drug Administration (FDA).

The future of the Cures Act may be largely dependent on who the next FDA commissioner is, noted to Arnie Caplan, of Case Western University, during Levines post-talk Q&A session.

Later that evening, it was Caplans turn to take center stage, with Chris Evans of the Mayo Clinic.

They were the main event, you might say. With a backdrop of Caplan and Evans as photo-enhanced boxers, the mood was light for their Friday night debate, entitled, MSCs are Not Stem Cells. Or, as Nerem put it, is an MSC a mesenchymal stem cells, a medical signaling cell, or a mediocre scientific concept.

By all accounts, they verbally fought to a draw. But who knows. Maybe there will be a rematch in 2018, when the Regenerative Medicine Workshop will return to Hilton Head (March 21-24).

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Regenerative Medicine Workshop, Part 21 - Research Horizons

Targeting cancer stem cells may be a more effective way to overcome cancer resistance and prevent the spread of squamous cell carcinoma the most common head and neck cancer and the second-most common skin cancer, according to a new study by cancer researchers at the UCLA School of Dentistry.

Head and neck squamous cell carcinoma is a highly invasive form of cancer and frequently spreads to the cervical lymph nodes. Currently, cisplatin is the standard therapeutic drug used for people with HNSCC. Yet, more than 50 percent of people who take cisplatin demonstrate resistance to the drug, and they experience a recurrence of the cancer. The five-year survival rates remain sorely low and researchers still dont understand the underlying mechanisms behind head and neck squamous carcinoma. Therefore, said UCLA cancer biologist Dr. Cun-Yu Wang, who led the study, theres an urgent need to understand why people with this type of cancer are resistant to therapy and to develop new approaches for treating it.

Wangs researchis published online today in the peer-reviewed journal Cell Stem Cell.

Cancer stem cells are known to be responsible for tumor formation and development; they also self-renew and tend to be unresponsive to cancer therapy. These cells have been found in head and neck squamous cell carcinoma. Given the unique challenges that cancer stem cells pose for oncologists, it remains unclear what the optimal therapeutic strategy is for treating HNSCC.

To address this, Wang, who holds the Dr. No-Hee Park Endowed Chair in Dentistry at UCLA and holds a joint appointment in the UCLA Department of Bioengineering, and his research team first developed a mouse model of head and neck squamous cell carcinoma that allowed them to identity the rare cancer stem cells present in HNSCC usingin vivolineage tracing, a method to identify all progeny of a single cell in tissues.

The researchers found that the cancer stem cells expressed the stem cell protein Bmi1 and had increased activator protein-1, known as AP-1, a transcription factor that controls the expression of multiple cancer-associated genes. Based on these new findings, the UCLA team developed and compared different therapeutic strategies for treating head and neck squamous cell carcinoma. They found that a combination of targeting cancer stem cells and killing the tumor mass, consisting of high proliferating cells, with chemotherapy drugs resulted in better outcomes.

The team further discovered that cancer stem cells were not only responsible for squamous cell carcinoma development, but that they also cause cervical lymph node metastasis.

This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice, said Wang, who is a member of the UCLA Jonsson Comprehensive Cancer Center and of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.

With this new and exciting study, Dr. Wang and his team have provided the building blocks for understanding the cellular and genetic mechanisms behind squamous cell carcinoma, said Dr. Paul Krebsbach, dean of the UCLA School of Dentistry. The work has important translational values. Small molecule inhibitors for cancer stem cells in this study are available or being utilized in clinical trials for other diseases. It will be interesting to conduct a clinical trial to test these inhibitors for head and neck squamous cell carcinoma.

Additional authors of the study include Demeng Cheng, first author and postdoctoral scholar in Wangs lab; Mansi Wu, Yang Li, Dr. Insoon Chang, Yuan Quan, Mari Salvo, Peng Deng, Dr. Bo Yu, Yongxin Yu, Jiaqiang Dong, John M. Szymanski, Sivakumar Ramadoss and Jiong Li who are all from the laboratory of molecular signaling in the division of oral biology and medicine at the UCLA School of Dentistry.

This work was supported in part by the National Institute of Dental and Craniofacial Research grants R37DE13848, R01DE15964 and R01DE043110.

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Targeting cancer stem cells improves treatment effectiveness and ... - UCLA Newsroom