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CCHMC, Specialty Pharma P2D Receive NIH Funding to Develop Pancreatitis Dx

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NEW YORK (GenomeWeb) – Following on the successful development of a genetic test for heritable jaundice, researchers from Cincinnati Children's Hospital Medical Center (CCHMC) and specialty pharmaceutical firm P2D have begun work on a next-generation sequencing assay to identify mutations associated with inherited forms of pancreatitis.

Meantime, P2D and CCHMC continue to work on a follow up to the jaundice test that will use next-gen sequencing to screen for genetic mutations in order to diagnose a number of additional liver diseases.

Pancreatitis — inflammation of the pancreas — is categorized as either acute or chronic, with the former typically caused by gallstones or alcoholism, and usually resolving with therapy.

Chronic pancreatitis, however, is a progressive disease that can result in permanent organ damage and is typically managed rather than treated. Though its causes are not fully understood, in recent years it has been linked to mutations in a number of genes, particularly in pediatric populations for whom environmental factors such as alcohol consumption are less likely to play a role.

As such, "the time is right to come up with a single assay that screens [for those] mutations," CCHMC researcher Jorge Bezerra, who is participating in the NIH-funded project, told GenomeWeb.

Previously, Bezerra and colleagues at P2D and CCHMC developed JaundiceChip, a diagnostic that runs on Affymetix's GCS 3000 GeneChip scanner that screens patient blood samples for the five most common genetic mutations in children with inherited causes of jaundice and is commercialized through the hospital's Molecular Genetics Laboratory.

Aiming to expand the utility of the product while taking advantage of newer technologies, the scientists began working on a LiverChip, which uses Illumina TruSeq next-generation sequencing technology to screen for mutations in an expanded panel of 12 genes associated with pathological jaundice, chronic liver injury, and cystic diseases of the liver.

This month, the team received an NIH grant, worth just over $566,000, to validate LiverChip in well-characterized patients for each of the test's target diseases, and to develop a software tool to streamline the analysis of the test's nucleotide readout in order to shorten the time to diagnosis.

Buoyed by the initial success transitioning from the Affymetrix platform to the Illumina platform, Bezerra and his collaborators, which include CCHMC's Maisam Abu-El-Haija, are aiming to apply the same approach to pancreatitis. They received an additional NIH grant, worth approximately $266,000, this month for that effort.

According to Abu-El-Haija, genetic screening for pancreatitis currently focuses on single genes, a time-consuming and expensive process. And while one company, Ambry Genetics, offers an assay that can screen for mutations in up to four genes, there remains a need for more comprehensive testing.

"There are different forms of the disease and we don't know exactly which gene mutations are associated with the more aggressive forms," she explained. Generating as much genetic data as possible on the etiology of chronic pancreatitis could help clinicians better understand a particular patient's disease and, potentially, allow for personalized treatment.

"Treatment right now is the same for every disease," Abu-El-Haija, said. "Hopefully in the future, when we understand the mutations, we can apply therapies toward those mutations." For instance, while mutations in the cystic fibrosis transmembrane conductance regulator, or CFTR, gene are responsible for cystic fibrosis, they have also been linked to chronic pancreatitis in patients who don't show any symptoms for cystic fibrosis. Experimental treatments that target such mutations may prove effective for these patients.

Thus far, the CCHMC and P2D investigators have analyzed the nucleotide composition of the six target genes for PancreasChip and have designed a one-step TruSeq multiplex test to generate amplicons for all exons and target intron-exon boundaries with greater than 99 percent coverage.

Under the NIH grant, they plan to generate amplicons in healthy control subjects and compare chip readouts with known sequences. They will then determine whether the sequence output produced by the PancreasChip detects insertions, deletions, or indels in DNA of patients with chronic pancreatitis.

As with LiverChip, P2D plans to commercialize PancreasChip, CEO Frank Zemlan told GenomeWeb in an email. He added that although the US Supreme Court's 2013 ruling that isolated gene sequences are not patentable, the company doesn't have any primary intellectual property around the approaches.

However, he wrote that "the expertise and cost of developing the test … is a sufficient barrier" to competitors.

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