Bench to Bedside

September 2013

Science and Medicine Feeling the Sequester’s Pinch


Every new medicine, medical technology, or treatment we rely on today — ones that we take for granted when we walk into a pharmacy to fill a prescription or to purchase pain relievers — stems from one collective source: research. It is intrinsic to the advancement of healthcare. Without research there would be no new treatments or cures.

Concerns about the impact of the sequestration on science have been gaining momentum in recent weeks. Recently, David Firestone of the New York Times wrote in the paper’s “Taking Note” blog that the sequester means that “science is falling behind, delaying promising results and discouraging young scientists, who are leaving the field.”

He further noted that the automatic, across-the-board federal budget cuts that are affecting myriad government agencies like the National Institutes of Health have “produced shock waves that will continue harming the country for years to come, because researchers operate on long-term schedules and need a reliable stream of revenue to produce results.”

The sequester could not be more ill-timed in the world of biomedical research. Now, as never before, investigators are embarking on a revolutionary period in science. We are harnessing the knowledge of the human genome, embracing cutting-edge technologies, and leading the way in “outside the box” thinking and research programs – all of which help improve the health of people around the world.

Programs like those at The Children’s Hospital of Philadelphia Research Institute and at hundreds of other hospitals, universities, and research centers around the United States are feeling the tremendous impact from the federally imposed sequester. Promising research projects are being shelved because of the funding cuts imposed by the sequester. And the sequestration may discourage the next generation of scientists. Many brilliant minds with budding research programs that could further advance science and healthcare are struggling to find a foothold on the shifting landscape of biomedical research.

In the end, the world’s population at large will suffer the greatest loss because it means the delay of new treatments and cures for diseases.

What can you do? Contact your senators and representatives and tell them that NIH funding is critical to the advancement of science and health for everyone. Tell them to stop the across-the-board cuts to NIH. Tell them your vote is at stake. The louder we speak, the greater impact we can have.

You can find your representatives and senators here.

Thank you!

Phil Johnson, MD
Chief Scientific Officer
Executive Vice President, Translational Medicine and Science
Director, The Children’s Hospital of Philadelphia Research Institute

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Preserving Prepubescent Boys’ Fertility


The good news is that more children survive cancer now than ever before, as doctors are able to cure nearly 80 percent of patients. But that doesn’t mean that those pediatric patients who survive cancer stop fighting once their treatment ends, because many face a variety of physical and emotional challenges as a result of their treatment.

The Children’s Hospital of Philadelphia’s Cancer Survivorship Program “helps patients and families navigate life after cancer, including both the physical and emotional issues they may have.” The program, which is led by Jill P. Ginsberg, MD, offers a variety of services and has a number of studies currently underway, including research into the neurobehavioral outcomes of acute lymphoblastic leukemia survivors, and key adverse events following childhood cancer.

Another research initiative, one targeting prepubescent boys who have been diagnosed with cancer, was the subject of recent media attention, with articles appearing in Nature Medicine and The Wall Street Journal. Led by Dr. Ginsberg and Thomas F. Kolon, MD, the experimental program seeks to collect and preserve testicular tissue from young boys who are set to receive cancer treatment, in the hope that their tissue could one day be used to produce viable sperm.

An estimated 35 percent of prepubescent boys are at risk of sterility following cancer treatment, Dr. Ginsberg said, and because prepubescent boys cannot produce sperm, CHOP’s testicular tissue cryopreservation (TTCP) program can offer families hope. Based on pioneering work by the University of Pennsylvania’s Ralph L. Brinster, PhD, the procedure involves the removal of a small amount of testicular tissue containing spermatogonial stem cells, “about half the size of a pencil eraser,” according to the Nature Medicine article.

The hope is that these stem cells can either be transplanted back into the boys to grow spermatogonial tissue following cancer treatment, or be used to grow sperm in vitro. However, because the procedure remains experimental, only boys at the highest risk for infertility are approached to take part in the program. Though researchers have yet to produce sperm using human spermatogonial tissue, work by Dr. Brinster’s lab has shown that the approach works in a mouse model.

Dr. Ginsberg has compared the development of TTCP to that of in vitro fertilization (IVF). IVF took 15 years to go from the lab to the birthing suite, Dr. Ginsberg pointed out, whose work on TTCP began in 2007.

“If everyone keeps saying ‘it’s too experimental,’ we’ll never get anywhere,” Dr. Ginsberg said in the Nature Medicine. “Everyone was saying IVF was too experimental years ago, and now it’s not. All of these things have to start somewhere.”

“Really Positive” Reaction

 However, there have been concerns associated with TTCP. In addition to the usual skepticism that accompanies any new research, there have been ethical concerns about the tissue removal surgery. In particular, there are worries that the surgery is too invasive, given TTCP’s experimental nature.

To allay these concerns, the tissue removal surgery is coupled with another regularly scheduled procedure. “We don’t want to expose the children to another general anesthesia since there is a risk with any general anesthesia, so we wanted to make sure it was coupled with another trip to the operating room,” Dr. Ginsberg said.

Indeed, according to a questionnaire handed out after the treatment, coupling the testicular tissue removal procedure with another has led some families to agree to take part in the program when they might not have been interested, Dr. Ginsberg pointed out.

Moreover, “even though this is experimental, and we basically tell the families that we’re not even sure the tissue will be usable for their children, 80 percent of the patients approached are agreeing to do the procedure,” Dr. Ginsberg said.

And thanks to a recent award from the St. Baldrick’s Foundation, the TTCP program is set to expand to two other institutions. For the first few years of CHOP’s TTCP work, Children’s Hospital was the only center that could accept patients and “we were getting calls from all over,” Dr. Ginsberg said, so she knew the work would be appealing to other centers. The $125,000 St. Baldrick’s grant will allow the Testicular Cryopreservation Consortium to expand beyond CHOP to include Seattle Children’s Hospital and Memorial Sloan-Kettering Cancer Center.

“We are hopeful that advances in the laboratory will make it possible for these boys to achieve fertility when they are ready to start a family. This work could not have been accomplished without the support of St. Baldrick’s Foundation,” said Dr. Ginsberg after the award was announced.

In addition to its groundbreaking work with prepubescent boys, Children’s Hospital also has a robust sperm-banking program for postpubescent boys. Every postpubescent boy set to be treated for cancer at CHOP is approached about banking, “independent of their risk,” Dr. Ginsberg said, noting that roughly 85% of boys agree to bank.

The Children’s Hospital of Philadelphia is one of few, if not the only, institution in country that approaches all postpubescent boys set to undergo cancer treatment, Dr. Ginsberg pointed out, and the program is “one of the programs here at CHOP that I’m most proud of.” And overall, families’ reaction to the TTCP program has been “really positive,” Dr. Ginsberg said.

To learn more about CHOP’s cancer treatment, survivorship program, and research, see the Cancer Center.

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Proton Therapy Offers New, Precise Treatment for Neuroblastoma


Proton therapy, which uses high-energy subatomic particles, may offer a precise, organ-sparing treatment option for children with high-risk forms of neuroblastoma, the most common solid tumor of early childhood. For patients in a new study of advanced radiation treatment, proton therapy spared the liver and kidneys from unwanted radiation, while zeroing in on its target.

Protons are the positively charged particles in an atom’s nucleus, and are used in therapy to destroy DNA in tumors and prevent cancer cells from multiplying. In children, this therapy is often used against spinal tumors. CHOP has recently been directing protons at neuroblastoma, long a special focus of the Hospital’s clinical and research programs.

Pediatric oncologists have an arsenal of weapons against neuroblastoma, but high-risk forms of this cancer present a particular challenge, often frustrating conventional treatment from the start or recurring in a resistant form.

The study included 13 children who responded well to initial chemotherapy, followed by surgery, more chemotherapy, bone marrow transplant, and, in some cases, immunotherapy. The advanced radiation treatment aimed to destroy remaining microscopic areas of cancer cells while minimizing toxicity to healthy tissue.

“As survival rates improve for children with neuroblastoma, we need to reduce treatment-related long-term toxicities,” said study leader Christine Hill-Kayser, MD, a radiation oncologist in The Children’s Hospital of Philadelphia’s (CHOP) Cancer Center. “Proton beam therapy offers precise targeting with less radiation exposure to healthy tissue.”

In planning radiation treatment for each child, the study team determined that 11 patients should receive proton therapy. The two other patients received intensity-modulated X-ray therapy (IMXT) because of the specific anatomy and location of their tumors. In IMXT, radiologists sculpt the radiation emitted from 7 different angles to modify radiation dosages in and around the targeted area.

None of the 13 patients had local disease recurrence or acute organ toxicity. For 11 of them, proton therapy provided the best combination of target coverage and organ sparing. “Protons are heavier than the particles in X-rays and have more stopping power,” said Dr. Hill-Kayser. “They deposit 90 percent of their energy precisely at the tumor site, with nearly zero radiation away from the tumor. That protects healthy organs—which, as growing tissues, are especially vulnerable to radiation damage in young children.”

The fact that individual characteristics made IMXT preferable to proton therapy in two children, said Dr. Hill-Kayser, underscores the need to meticulously customize radiation treatment to each patient. Overall, the current study shows that proton therapy should be considered for children with high-risk neuroblastoma. She added, “To better assess the use of proton therapy against high-risk neuroblastoma, we’ll need to study larger numbers of patients and do long-term follow-up. However, this represents a great start.”

Owing to collaboration between Children’s Hospital and radiation oncologists at Penn Medicine, the Roberts Proton Therapy Center, where the study was conducted, is the first proton therapy facility in the U.S. conceived with pediatric patients in mind from the earliest planning stages.

The co-authors of this study were Robert Lustig, MD, Zelig Tochner, MD, and Stefan Both, PhD; like Hill-Kayser, all are from the Department of Radiation Oncology of the Perelman School of Medicine at the University of Pennsylvania. Co-authors Anne Reilly, MD, Naomi Balamuth, MD, Richard Womer, MD, John Maris, MD, Stephan Grupp, MD, PhD, and Rochelle Bagatell, MD, are from the Cancer Center for Children at CHOP.

Dr. Hill-Kayser and colleagues published their study online June 4, 2013, in the journal Pediatric Blood & Cancer. More details on the study are available here.

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New Partnership Will Expand Ways to Move Research to the Marketplace


Investigators at Children’s Hospital work tirelessly to uncover the inner workings of biological systems and the causes of diseases. But making discoveries is only part of the challenge; the next set of challenges often lies with taking the new knowledge from discoveries and working with outside partners to bring promising new therapeutics and treatments to patients.

A partnership between Children’s Hospital and the venture-capital firm Osage University Partners (OUP) will expand the opportunities to commercialize the research done at Children’s Hospital, moving the potential for new treatments even closer to patients’ bedsides.

OUP invests exclusively in startup companies that commercialize academic research. It shares part of the resulting profits with those institutions to further promote entrepreneurial opportunities within those centers.

OUP is part of Osage Partners, a family of venture capital funds based in Bala Cynwyd, Pa. OUP has research partnerships with more than 60 universities and research centers, including the University of Pennsylvania, Johns Hopkins University, Carnegie-Mellon University, Drexel University, and Duke University.

The company invests in life sciences, biopharma, and medical devices and diagnostics, in addition to other industries such as those involved in information technology, energy and materials technology. It typically co-invests in conjunction with other venture companies.

“This partnership offers a mechanism to move our Hospital’s innovative research into the marketplace and better provide health benefits to children and families worldwide,” said Philip R. Johnson, MD, chief scientific officer and executive vice president at The Children’s Hospital of Philadelphia.

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Gene Variants Identified in African American Blood Pressure Study


A new study detailing the largest-ever genetic analysis of blood pressure in African Americans has identified five gene variants linked to the trait. According to the study, which was published recently in the American Journal of Human Genetics, three of the gene variants have not previously been implicated in blood pressure, and represent novel findings.

“High blood pressure occurs in roughly 40 percent of African Americans, which is a much higher rate than in other U.S. ethnic groups, and adds a significant risk to the development of cardiovascular disease,” said one of the co-senior authors of the paper, The Center for Applied Genomics geneticist Brendan J. Keating, DPhil.

“The discovery component of this study included data from nearly 30,000 African American individuals,” said Dr. Keating. In the replication phase, the researchers validated the findings in over 100,000 individuals of different ancestries.

While the research findings do not have immediate implications for treatment, the hope is that discovering genes associated with disease risks will bring scientists closer to biological pathways and may suggest useful drug targets for new treatments.

The other two senior co-authors of the study are Xiaofeng Zhu, PhD, of Case Western Reserve University, Cleveland, and Nora Franceschini, MD, MPH, of the University of North Carolina, Chapel Hill. There were dozens of co-authors in this meta-analysis, which combined data from 19 cohorts of adult subjects who contributed their DNA to previous genome-wide association study analyses.

Three of the variants discovered in the African American samples, in the genes EVX1-HOXA, RSPO3 and PLEKHG1, had not previously been reported for blood pressure. Two other gene variants in those subjects had previously been discovered in patients of European ancestry.

“These findings actually explain only a very small portion of the genetic variation that we know underpins blood pressure in individuals of African ancestry, so further independent studies need to be added to these efforts to discover even more variants,” said Dr. Keating. “Gaining more biological knowledge of the factors underlying blood pressure levels will help us to obtain new insight into the development of hypertension and to identify potential new drug candidates for therapy.”

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Surgery Improves Outcomes for Children with Obstructive Sleep Apnea


Sleep experts have conducted the first multicenter clinical trial of obstructive sleep apnea in children and have found that those who underwent surgery to remove their adenoids and tonsils had notable improvements in behavior, quality of life and other symptoms compared to those treated with “watchful waiting” and supportive care.

However, the researchers found no difference between both groups in attention and executive functioning, as measured by formal neuropsychological tests.

“This was the first randomized clinical trial of surgery for obstructive sleep apnea in children,” said first author Carole L. Marcus, MD, who directs the Sleep Center at The Children’s Hospital of Philadelphia. “Some previous, smaller studies had found this condition associated with cognitive and behavioral problems, including ADHD, so it was important to do a controlled trial to evaluate the benefits of surgery, which is a common treatment.”

The findings are the result of the Childhood Adenotonsillectomy Trial (CHAT) that involved 464 children, aged 5 to 9, at seven academic sleep centers. The CHAT researchers published their findings in the New England Journal of Medicine, in conjunction with a presentation at the American Thoracic Society annual meeting. Susan Redline, MD, MPH, of Brigham and Women’s Hospital, Boston, is the study’s principal investigator.

Obstructive sleep apnea syndrome, or OSAS, is a condition of interrupted breathing caused by a narrowing in the throat or upper airway, resulting from enlarged tonsils and adenoid, obesity or other medical problems. Occurring in both adults and children, OSAS has a higher prevalence in African-American and obese patients. Adenotonsillectomy, the surgical removal of adenoid and tonsils, is the primary treatment for OSAS in children. More than half a million U.S. children undergo the surgery each year.

The primary outcome of the CHAT trial was the Attention/Executive Function Domain score in a formal test, the Developmental Neuropsychological Assessment. The study found no significant difference between the treatment groups in these test results. The secondary outcomes included ratings from parents and teachers who completed questionnaires rating a child’s behavior, sleepiness, quality of life, and executive functioning, including details about activities of daily living.

The researchers found that the children who had surgery had significantly greater improvements, compared to children in the watchful waiting group, in the secondary outcomes.

Overall, both surgery and watchful waiting were safe in this clinical trial, the researchers noted. Dr. Marcus said that watchful waiting was a reasonable option for parents of children with less severe OSAS who opt not to have surgery, but that clinicians should carefully monitor these children to ensure their condition does not worsen.

More research is needed to determine, among other things, the most effective treatments for younger children with OSAS and if the condition recurs as children enter puberty.

“Sleep medicine is a very new field, with many unanswered questions,” concluded Dr. Marcus. “For instance, we go to sleep each night, yet we don’t even know truly understand the true purpose of sleep. But this study is a great first step in finding some of the answers.”

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Groundbreaking Immune Therapy Featured on 60 Minutes Australia


The groundbreaking immune therapy work being done by The Children’s of Hospital of Philadelphia’s Stephen M. Grupp, MD, PhD, was recently highlighted on Australia’s 60 Minutes. The Center for Childhood Cancer Research’s Director of Translational Research, Dr. Grupp has seen encouraging early results of a trial using immune therapy to treat an aggressive form of childhood leukemia, acute lymphoblastic leukemia (ALL).

The most common form of childhood leukemia, ALL is largely curable, with approximately 85 percent of patients able to be cured. However, the remaining 15 percent of ALL cases resist standard therapy.

The 60 Minutes report focused on the researchers’ use of a ‘de-weaponized’ form of the HIV virus to deliver therapy. The HIV virus “is a terrible virus,” Dr. Grupp said on 60 Minutes, “but there’s a good property, and the good property of the virus is its ability to put a gene into cells. We isolate just that property and we get rid of all of the bad stuff, so yes, HIV’s been retasked to do good in this kind of treatment.”

In Dr. Grupp’s trial, which builds on an ongoing collaboration with Penn Medicine investigators, a type of white blood cells, T cells, are modified to attack cancer cells. Chimerican antigen receptor T cells are engineered to specifically target B cells, which can become cancerous in leukemias like ALL. After being returned to the patient’s body, the modified cells multiply thousands of times and circulate throughout the body, and persist for months afterward, guarding against recurrences.

Both the CHOP and Penn teams have seen great success with the treatment. At CHOP, two children with ALL achieved complete responses after being treated with the engineered T cells, while Penn researchers reported on the approach’s use in adults with another form of leukemia, chronic lymphocytic leukemia.

One of the patients treated in Dr. Grupp’s trial, young Emily Whitehead, remains healthy and cancer-free since receiving the innovative immune therapy. “I think we’re winning, we’re winning every day, I’m thankful for every day we have,” said Emily’s father Tom during the 60 Minutes piece.

“I believe that this may actually be revolutionary in cancer therapy, but we have to prove it. And we have to show that it can work in other kinds of cancer,” Dr. Grupp noted. “In general change in clinical medicine is one step at a time … but this seems to be at this point a big step forward.”

To watch the full 60 Minutes report on this groundbreaking form of immune therapy, click here.

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Orphan Disease Center Seeks to Expedite Orphan Disease Treatments


Orphan diseases represent a collection of disorders that afflict less than 200,000 individuals for any single disease type, yet there are more than 7,000 distinct orphan diseases. In the aggregate, over 25 million people in the United States suffer substantial morbidity and mortality from orphan diseases. Despite this huge number, research in most disease types has lagged far behind other major areas due to a combination of technological and funding limitations.

Recognizing these challenges, the Penn Center for Orphan Disease Research and Therapy (CODRT) was formed with the mission of facilitating and expediting the development of novel therapies for orphan diseases. The Center will achieve this mission through promoting development of novel therapeutic strategies and translating these into the clinic, building on partnerships among investigators, academic institutions, industry, and federal and private funding agencies.

The Penn Center for Orphan Disease Research and Therapy invites faculty members at Penn and CHOP who conduct research in rare diseases to join the Center. The CORDT will provide resources and funding opportunities to Center members with demonstrated expertise in rare disease research and/or therapy development. Trainees interested in rare disease research can join as Associate members. Center membership will provide:

For membership information, please click here.

Research Funding and Events

The Center for Orphan Disease Research and Therapy has also announced a Request for Applications to support research on the development of improved therapies for patients with syndromes due to MPS I including Hurler, Hurler-Scheie, and Scheie. Particular emphasis will be placed on treatments that improve aspects of the disease that are not adequately treated by enzyme replacement therapy such as pathology in the CNS, skeletal system, eye, and heart, among others.

To learn more about research funding opportunities through the CORDT, see the Center site.

The Center is also set to host a number of upcoming events. On Thursday, November 21, the Center will hold its first annual retreat, “Charting Paths Forward in Rare Diseases.” The day will start with an overview of the center followed by presentations on Center partners and opportunities in rare disease research, drug development, and biomarker discovery.

Guest speakers will include John F. Crowley, JD, MBA, chairman and CEO of Amicus Therapeutics; Larry Gold, PhD, chairman, founder, and CEO of SomaLogic, Inc.; Stephen C. Groft, PharmD, director of the NIH Office of Rare Diseases; John C. McKew, PhD, chief of the  Therapeutics Development Branch at the NIH Center for Translational Therapeutics; Bill Leinweber, president and CEO of the National Disease Research Interchange; and Dave C Schultz, PhD, facility director of the Wistar Institute’s Molecular Screening Facility.

And in the Spring of 2014, the Center will sponsor two events to focus awareness on orphan diseases and research. On Friday, May 2, 2014 we will hold the First Annual Symposium on Orphan Diseases followed by a Cycling Event for Rare Diseases on Saturday May 3. Beginning and ending on the University of Pennsylvania campus, the cycling event is designed to raise money and awareness for international rare disease research.

For information and registration, please click here.

To read more about the Penn Center for Orphan Disease Research and Therapy, please visit the Center site.

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