CHOP Innovates in Gene Therapy: Pennsylvania and Ohio Emerging Gene Therapy Research Hubs

CHOP Innovates in Gene Therapy Pennsylvania and Ohio's Emerging Gene Therapy Research Hubs

Children’s Hospital of Philadelphia (CHOP) reports a breakthrough in developing adeno-associated viral (AAV) vectors as a groundbreaking clinical tool for gene therapy and gene editing. Announcing a novel, more sensitive method for capturing the footprint of AAV vectors, they also reported in a press release a broad range of sites where the vectors transfer genetic material.

CHOP articulates that by capturing the full range of gene expression patterns caused by AAV vectors, the technique could advance the rapidly developing gene therapy field. CHOP’s most recent study results were published in Nature Communications.  The lead researcher is Beverly Davidson.

Research Center Spheres of Influence

TrialSite News has commented on the gene therapy leadership of Nationwide Children’s Hospital, possibly positioning Columbus, Ohio as the gene therapy capital of the world. Several breakthroughs came out of Nationwide Children’s Hospital, including billion dollar stories, such as Novartis’ purchase of Zolgensma, a spinal muscular atrophy (SMA) treatment that was associated with the Columbus institution.

But Dr. Beverly Davidson (founder of Spark Therapeutics, currently in the acquisition process with Roche) and Philadelphia P gains speed and momentum. CHOP, an elite institution that TrialSite News covers often, positions nicely in the biomedical corridor of the Tri-State region.

Summary of CHOP Innovation

AAV vectors are bioengineered tools that utilize harmless viruses to transport modified genetic material safely into tissues and cells impacted by otherwise difficult-to-treat conditions. The vectors deliver the “genetic cargo” into tissues, after which the modified genes will create new instructions for those tissues and help treat the disease. CHOP has been a true gene therapy hub. By using the vector technology developed at CHOP, they are responsible for the the first FDA-approved gene therapies, including Kymriah for B-cell acute lymphoblastic leukemia and Luxturna for inherited retinal disease.

Understanding Genetic Cargo Delivery Routes & Locations

Conventional methods to define gene transfer rely on fluorescent reporter genes that glow under a microscope, highlighting cells that take up and express the delivered genetic material. This approach involves limitations as only cells with stable, high levels of cargo appear—there isn’t 100% coverage.

CHOP researchers have developed novel technology to improve detection where the cargo is expressed—even if expressed at extremely low levels or only for short periods of time.

Beverly L. Davidson, Chief Scientific Strategy Officer at CHIP and Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, notes, “Conventional screening methods miss transient or very low levels of expression from AAV viral vectors” and went on to say that “this study shows that AAV vectors lead to a gene transfer in many more places than we and other groups initially realized.”

With Davidson at the helm, CHOP developed a new AAV screening method utilizing sensitive editing-reporter transgenic mice that are marked even with a short burst of expression or very low expression. In a side by side comparison with convention screening methods, the new approach radically redefines the true extent of AAV-mediated gene transfer.

Multiple Benefits

First and foremost is safety. As the sites where the vector expresses the modified gene are better defined, treatment becomes more accurate, possibly transcending existing knowledge about doses, etc. And because high and stable expression levels are not required for effective gene editing, dose levels that would not be ideal for more stable expression might work very well for genome editing. Moreover, this method expands the utility of the platform by revealing new, never-before-described sites of gene transfer in a way that heretofore was not possible with the existing baseline approach. CHOP also states that researchers now will progress understanding of basic biology of AAV vectors and what is required for them to effectively deliver their genetic payload—better knowledge leads to more granular effectivity.

Opening the Door for CRISPR Advancement

With the discovery of the CRISPR/Cas9 gene editing technology, the recent CHOP advancement offers relevance as thorough research of the genetic cargo is extremely important and opens the door to a new degree of precision medicine. CHOP notes in its press release that CRISPR/Cas9 gene editing machinery, when expressed in cells even for a short time or at low levels, permits targeted DNA editing.

Many groups seek to use AAV vectors to deliver CRISPR/Cas9 due to its track record as a safe vehicle for gene transfer. But because of methodological limitations, CHOP reports many sites of low-level gene transfer have been and will be missed with the existing approach. Now, combining AAV with gene editing machinery requires a more sensitive method for safe and effective applications.

Study Funders


Dr. Davidson is a founder of Spark Therapeutics and Talee Bio, Inc. and is on the advisory boards of Homology Medicines, Prevail Therapeutics, Sarepta Therapeutics, Intellia Therapeutics and Axovant Gene Therapy.

Lead Research/Investigator

Beverly Davidson