The Cornerstone of Personalized Medicine

The Cornerstone of Personalized Medicine

Personalized medicine: it’s all about you.

The idea of “personalized” medicine isn’t just about a one-on-one encounter with a doctor, the use of sophisticated mobile applications, or heightened access to healthcare providers, medical records, and services. Personalized medicine also extends into the depths of who each of us are at our essence — to our individual genetic makeup.

Why does this matter? Because now, more than ever before, rapid technological advances and scientific breakthroughs mean we know more about how genes may point to a predisposition for developing certain diseases. By understanding the cause of a disease, rather than focusing solely on its symptoms, we have far greater opportunities to try to delay the onset of a disease — or prevent it altogether.

Understanding our genetic makeup also sheds light on why a medicine may work well in one person but be ineffective in someone else with the same condition. Armed with this information, doctors can tailor treatments to those that carry the greatest chance of success based on a patient’s genetic predisposition.

A relatively new field of study, personalized medicine rocketed onto the scene after the completion of the Human Genome Project in 2003, the ambitious multi-billion-dollar federal initiative that analyzed 3 billion chemical base pairs involved in DNA and provided the genetic makeup of humans.

“On its surface, the concept of personalized medicine may seem complicated and perhaps a bit futuristic, but it’s far more science than science fiction,” says Philip R. Johnson, MD, chief scientific officer at the CHOP Research Institute. “It’s here now, and it is expanding what scientists understand about disease and changing the ways we care for patients.”

And, as in many areas of investigation, research conducted within the Centers of Emphasis at The Children’s Hospital of Philadelphia Research Institute serves as the cornerstone of this new foundation in personalized healthcare.

Building a Knowledge Base

Building a Knowledge Base

The hunt for genes associated with various diseases at the CHOP Research Institute often starts with the Center for Applied Genomics (CAG). Using state-of-the-art technology and techniques, the CAG team tirelessly searches for the genes underlying diseases to prevent and treat pediatric illnesses.

The progress CAG has made in the mere six years since it was formed is nothing short of astounding. The Center has one of the world’s largest programs for genotyping, the technical term for detecting gene variants and linking them to diseases. And CAG’s efforts are not only focused on common pediatric diseases like diabetes, autism, ADHD, and cancer, but numerous rare ones as well.

“In a very real sense, we are on the cusp of a new era where the combination of biology and technology is about to transform our understanding of pediatric disease,” says CAG director Hakon Hakonarson, MD, PhD.

In addition, CAG operates the world’s largest pediatric biorepository, collecting and organizing more than 150,000 specimens and providing a centralized and efficient resource for investigators across the Research Institute conducting their own studies.

During FY2012, the Center for Applied Genomics made significant advances in understanding the genetic underpinnings of ADHD, autism, and obesity, among others, and launched a new initiative aimed at gaining a better understanding of the genetic underpinnings of rare diseases.

Reading the Blueprints of Common Diseases

Reading the Blueprints of Common Diseases

Although the Center for Applied Genomics has numerous active genomics studies underway, in the last year the Center made groundbreaking discoveries on some of the most common diseases and conditions affecting children, most notably attention-deficit/hyperactivity disorder (ADHD) and obesity.

The CAG team, as well as that of the Center for Biomedical Informatics, collaborated with child psychiatrist Josephine Elia, MD, on the study of the genetic influences of ADHD, a common but complex neuropsychiatric disorder of unknown etiology. The focus of the study centered on copy number variations, or CNVs, which are segments of chromosomes of variable size where DNA has been deleted, duplicated, or rearranged.

The team found alterations in specific genes, called GRM genes, involved in important brain signaling. These genes come into play in up to 20 percent of children with ADHD. This new discovery made by CAG investigators may lead to new drugs and therapies that target those pathways, possibly offering new treatment options to more than a million children in the U.S. alone who have those gene variants.

Specifically, Children’s Hospital investigators are eyeing the redevelopment of a medication previously used for another condition that targets the GRM network, providing a much-needed alternative treatment approach for that subset of children with the ADHD gene variants who have not responded well to existing treatments. This innovative, genomics-based “test and treat” approach may represent the first personalized therapeutic for a neuropsychiatric disorder.

As prevalent as ADHD has become, perhaps equally prevalent are the number of childhood obesity cases in the United States and across the globe. Obesity is one of the major health issues affecting modern societies, and has grown to astronomical levels in the last decade among adults and children alike.

Although environmental factors like food choices and sedentary habits are key players in the condition, there is far more to obesity than that.

In FY12 CAG investigators led by Struan F.A. Grant, PhD, associate director of the Center for Applied Genomics, conducted the largest genome-wide study to date on childhood obesity. What they found was at least two new gene variants that increase the risk of the condition.

The approach taken by Dr. Grant and his colleagues diverged from previous studies that focused on gene variants associated with extreme obesity in adults and children. Despite possessing the largest collection of DNA from children with common obesity, the investigators broadened their study and formed an international consortium to combine the results from similar datasets from around the world.

The team identified two novel loci — one on chromosome 13 and the other on chromosome 17 — implicated in obesity, and found evidence that suggests at least two other gene variants are at play.

“This work opens up new avenues to explore the genetics of common childhood obesity,” says Dr. Grant, who added that the findings may one day lead to the development treatments and preventive interventions based on a children’s individual genomes.

Fortifying the Data Structure

Fortifying the Data Structure

Every study produces mounds of data to be sifted through, organized, and made sense of before conclusions can be drawn, implementations made, and results ultimately applied to clinical care.

Having the infrastructure and the knowledge base to take genomic information from the lab and apply it to clinical and diagnostic settings requires more than sophistication and expertise. It also requires an enterprise-level approach, one that is provided by the Center for Biomedical Informatics (CBMi).

Led by Peter White, PhD, CBMi develops innovative solutions that address the informatics needs of the Research Institute — and beyond. It provides the aptitude and infrastructure critical to maximizing the value of the data and other information relevant to research and clinical activities at Children’s Hospital.

Put more simply, CBMi’s expertise in medicine, biology, statistics, mathematics, linguistics, and computer science empowers it to help investigators, clinicians, and families alike best use the ever-evolving and expanding pediatric health information.

CBMi is also uniquely positioned to integrate the Hospital’s genomics capabilities into daily clinical practice. The Center explores how to merge genomic, clinical, and other data into existing systems — like the electronic health record — that can be powerful tools for healthcare providers. Indeed, the Center has a new director of Genomic Medicine, Patrick Warren, PhD, who helps meet the increasing needs of personalized genomics at CHOP by working with researchers, clinicians, regulatory groups, and informaticians to incorporate genome-based discoveries into the electronic health record through clinically governed decision support systems.

But the Center’s efforts don’t stop there. CBMi’s work includes zeroing in on the most effective ways of presenting the results of genomics studies to clinicians, patients, and families; providing the structure and support for genetic counselors to use creative informatics solutions; and taking a close look at the ethical implications of making genomic data available in a patient’s electronic health record.

“CHOP’s recent high volume of breakthroughs in genomics research is a direct results of its thoughtful approach to translational science,” says Dr. White. “CBMi will further develop the infrastructure and knowledge needed to fully support clinical and diagnostic genomic medicine practices throughout the Hospital.”

In FY12, the Center continued its collaboration with the Department of Pathology and Laboratory Medicine to develop genomic sequencing-based diagnostics tests for a variety of conditions. In April, the Hospital’s first whole genome sequencing-based diagnostic test was introduced for Noonan syndrome, a congenital disease linked to a number of symptoms, including developmental delays, short stature, distinctive facial and body features, and cardiac issues.

CBMi is also heading a key project on the sequencing, analysis, and interpretation of data on the recently awarded $2.2 million Clinical Sequencing Exploratory Research Project. One unique tool already being put to use, called Varify, gives healthcare providers and researchers a quick overview at suspected genetic variants for a sample.

“Overall, this project will build a framework for systematically assessing the gene sequence data we collect, to integrate the data with medical care,” Dr. White says. “We envision Children’s Hospital as a ‘working lab’ of sorts to combine genomic analysis with our clinicians’ observations and diagnostic expertise to support physicians and families in making healthcare decisions.”

Framing the Issues Underlying Rare Diseases

Framing the Issues Underlying Rare Diseases

In FY2012, the Center for Applied Genomics teamed up with Beijing, China-based BGI, the world’s largest genomics organization, to launch the 1,000 Rare Diseases Project. The project aims to accelerate the discovery of genetic variants underlying rare diseases — often life-threatening or chronically debilitating ailments.

Despite the thousands of rare diseases in the world, patients with these diseases are an exceptionally underserved population. Although affecting approximately one in 12 newborns, the number of patients with a specific rare disease is usually small; therefore, these patients often lack the social and medical support available to others with more common conditions.

On top of that, the relatively small number of patients with a particular rare disease unfortunately also means that it’s difficult for research organizations to justify investing limited research dollars to understand and treat a disease that affects so few.

CHOP and BGI are tackling this problem by using next-generation sequencing technologies to analyze DNA samples from patients and families who have donated samples to the CAG biorepository.

“The most accurate and efficient way to achieve this goal is to sequence genomes of affected children, as well as their first-degree relatives,” says Dr. Hakonarson, who adds that the project will ultimately provide a solid genetic foundation for future clinical diagnosis and treatment for those with rare diseases, and in some instances, may inform therapies for more common complex diseases.

Interpreting the Genetic ‘Plan’

Interpreting the Genetic Plan

With more and more DNA sequence data generated every day, revealing new versions of genes and other genetic variants, a host of questions has arisen about what to do with the information. How much is clinically relevant? How should it be integrated into practice? And how should this information be shared with patients?

And that’s just on the healthcare side. What about patients and their families? Would they want to know about their child’s genetic predisposition to a disease? Supposing parents decided to have their child’s genome sequenced to determine a predisposition — would they make different decisions today based on what might happen tomorrow?

An innovative project at Children’s Hospital seeks to look beyond the massive data surge to consider the ethical issues accompanying knowledge that comes from the sequencing of an individual’s genome.

Children’s Hospital is one of six U.S. centers, and the only one focused exclusively on pediatrics, to receive a Clinical Sequencing Exploratory Research Project award from the National Human Genome Institute. The $2.2 million four-year award was made to the husband and wife team of Ian D. Krantz, MD, and Nancy B. Spinner, PhD.

In addition to examining the ethical issues associated with clinical sequencing, the consortium will propose guidelines on sharing, interpreting, and using genetic information. The Center for Biomedical Informatics leads the critical informatics component of this ambitious project. The consortium’s work will then help physicians, healthcare professionals, and genetic counselors best interpret the data for patients and their families.

“Currently, when gene analysis helps us arrive at a diagnosis of a child’s disorder, we can counsel a family, providing information about what to expect and what options may be available for therapy and medical intervention,” says Dr. Krantz, who notes that genome-wide sequencing can also uncover “incidental findings” — gene variants that are not related to a current condition but may have a bearing on a patient’s future health.

However, only a handful of the thousands of gene variants in a person’s genome will be clinically significant or actionable, giving physicians greater knowledge to suggest medical interventions, if warranted.

“By the end of this decade, we anticipate that genomic sequencing will be readily available for the diagnosis of pediatric disorders,” Dr. Krantz says. “Our goal is to help make the information-sharing process systematic, thoughtful, and sensitive to the needs and desires of patients and families.”

The Next Level: Direct Patient Care

The Next Level: Direct Patient Care

Cancer. It’s a small word, but one that sure bears a hefty punch.

Only a few decades ago, cancer in children was usually fatal. Thankfully, that’s not the case anymore, and there is tremendous reason for hope. Advances in research and treatment approaches have led to a far greater understanding of the myriad issues surrounding cancer, and cure rates have reached an all-time high.

But a cancer diagnosis continues to instill fear. Parents are rightfully concerned about both the short- and long-term negative affects of chemotherapy or other treatments their children may need to undergo — and there are no guarantees that a standard treatment will work.

And then there are discoveries that take cancer care and treatment to a whole new level, providing even greater hope for patients and their families.

In FY12, Children’s Hospital investigator and oncologist Yaël P. Mossé, MD, made headlines around the world with news that a drug originally developed for use in adults with lung cancer showed amazing results in early trials in children with two aggressive forms of cancer — anaplastic large-cell lymphoma (ALCL) and neuroblastoma.

The drug, called crizotinib (brand name Xalkori®), was approved by the Food and Drug Administration in 2011 to treat late-stage non-small cell lung cancers in patients who express a gene called anaplastic lymphoma kinase (ALK). Just three years earlier, Dr. Mossé and her team in the Center for Childhood Cancer Research discovered that mutations in the ALK gene were implicated in 10 to 15 percent of the cases of neuroblastoma, the most common solid cancer of early childhood.

Once crizotinib hit the market, Dr. Mossé was able to expedite her phase 1 clinical trial, bypassing the extensive early development stage that is typical for most new drugs. The results were astounding, and highly encouraging.

Dr. Mossé gave crizotinib to eight children with ALCL whose cancer was not responding to traditional chemotherapy. Within days of receiving crizotinib, an oral medication, seven of the patients found that their fever and chills went away and their pain had significantly lessened or disappeared altogether.

But even more impressive were the subsequent imaging scans that showed no trace of cancer in the patients.

While further investigations are needed to determine the effectiveness and appropriate dose of crizotinib, Dr. Mossé ‘s study underscores the tremendous promise of personalized medicine, even for the sickest of patients with among the most complex and aggressive diseases.

“We are entering a new era of cancer therapy, in which we use knowledge of basic biology to design very specific drugs that target cancer cells with few side effects on healthy tissue,” Dr. Mossé says. “In addition, as we concentrate on targets in molecular pathways, we move away from an exclusive focus on one form of cancer to customizing treatments according to biological activity.”