Rare Disease Research at the Center for Applied Genomics at CHOP


Discovering the genetic variants that cause rare disease are essential to delivering better diagnoses, improved treatments, and preventive medicine. The most accurate and cost-effective method of achieving this goal is to sequence the genomes of affected patients, as well as their first-degree relatives. At the Center for Applied Genomics (CAG) at the Children’s Hospital of Philadelphia, we have launched an innovative initiative aimed at identifying the cause of, and treatments for hundreds of rare diseases.

The initiative has its roots in another large-scale project launched at the Center in 2006 – to collect and analyze medical data and blood samples from more than 100,000 children. Currently almost 70% towards this total, the database constitutes the largest pediatric biobank in the world. By extension, it is also one of the largest rare disease repositories – with some 6,500 samples represented, and a further 10,000 available via collaborations in the US, South America, Europe and Australia. Our goal in the next five years is to sequence the genomes of the majority of these patients.

In tandem with the genome sequencing effort, CAG has also established a major translational research program, whose primary purpose is to identify drug treatments for relevant rare disorders. The sequencing and translational program are natural allies – once the causal genetic factor is identified, it is essential that we move quickly to find an effective treatment. In terms of rare-disease, the most cost-effective and time-efficient approach is to identify drugs that have already been developed. Every drug that has reached the stage of clinical trials has an existing literature, which outlines molecular properties of the drug and clues as to its effects on physiology.

By matching the biological function of a damaged gene with the biological properties of an existing medication, we can come up with a targeted treatment – a pharmacological intervention tailored specifically to match the mal-functioning gene.  Often this involves drug repositioning, meaning that we take a medication previously developed to treat one disorder and applying it to an entirely different disorder. By way of example, researchers at CAG are currently working on a program that utilizes a drug developed to treat Alzheimer’s and applying it as an intervention in rare forms of ADHD.

Another component of our translational program involves studying the function of the mutated gene in model systems such as cell cultures, to determine relevant physiological properties. While this component may not have the same immediate impact, it is essential to understanding the course of the disease, and will ultimately yield long-term benefits in terms of disease management, and refining treatments.

Recent developments in technology and analytical software allow us to pursue our sequencing and translational efforts with ambitions scarcely conceivable a decade ago. The first human genome sequenced was done so at a cost of several hundred million dollars. At CAG, we can now accomplish the same feat for roughly $5,000. As such, we can sequence a patient as well as first-degree relatives (important to zeroing-in on the causal locus) for less than $25,000. For roughly the same cost, we can perform the requisite analyses for determining the causal genomic locus.

Although these are non-trivial amounts, they are dwarfed by the huge investments required to accomplish similar results in the very recent past. We believe that the time is now right to launch a major offensive on rare disease – never before have the instruments of success been so readily available.
The Center has instigated a major fund-raising initiative, which will allows us to sequence the majority of samples in our repository, with the ultimate end-goal of translating relevant findings into targeted treatments.

To this end, we hope to partner with the RARE Fund, which represents a paradigm-shift in terms of how this type of research may be funded, and represents an exciting opportunity of bringing non-scientists into the fold of cutting-edge research.

If you have any questions about the Center or our program, please feel free to contact me (connollyj1@chop.edu), or check-out our website at www.caglab.org.

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