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BGI 'Interested' in Combining Exonhit's SpliceArray with Sequencing Efforts for Biomarker Discovery


By Justin Petrone

A new collaboration between BGI and Exonhit Therapeutics could breathe new life into Exonhit's splice variant microarray platform.

Officials from both organizations said this week that they are keen to use Exonhit's SpliceArray platform in new, sequencing-driven biomarker discovery projects.

"SpliceArray is a very good platform to understand gene regulation and very useful for biomarker development," said BGI spokesperson Bicheng Yang. She said that the Shenzhen-based genomics institute is "interested in combining this platform with BGI's tech platforms to explore more pharma-related applications."

In terms of technology, BGI is primarily known for its fleet of next-generation sequencing instruments. Through its headquarters and regional offices — BGI Hong Kong, BGI Europe in Copenhagen, Denmark, and BGI Americas in Boston — the institute provides sequencing services on systems sold by Life Technologies, Roche 454, and Illumina. It ordered 128 HiSeq systems from Illumina last year.

Still, BGI sees value in using array-based tools such as SpliceArray. Yang said that BGI Europe recently approached Paris-based Exonhit to access SpliceArray to achieve a more "comprehensive understanding of gene deregulation" and to "develop biomarkers and molecular diagnostic tests for complex diseases."

In a statement, Exonhit said the partners recently completed a study that combined massively parallel sequencing and SpliceArray to identify novel biomarkers in a "strategic preclinical animal model species."

The company said the project "captured novel gene expression for a model species key for preclinical therapeutic development in certain indications with unmet medical need," but did not disclose additional details.

The project was the first such partnership for BGI and Exonhit. According to Matthew Pando, executive vice president of therapeutics at Exonhit, the cooperation resulted in a new, custom version of the firm's SpliceArray that contains sequence information relevant to the model species in the study.

"Exonhit views [next-gen sequencing] as a complementary discovery platform capable of producing comprehensive transcript data for species or samples with poor publically available sequence coverage," Pando said. "This project did just that and allowed us to then build a comprehensive custom SpliceArray for an important model species that could not be produced with access to only publically available sequence data."

According to Pando, the new SpliceArray's content conforms to the firm's existing probe layout, which "allows us to monitor directly all of the exon bodies, exon-exon boundaries, and exon-intron boundaries of every identified transcript."

The chip will now be used to "support target and biomarker-discovery efforts for projects of strategic importance to Exonhit," Pando said. When asked about SpliceArray's advantages compared to a solely sequencing-based approach, Pando cited "reduced cost per sample, lower RNA amounts needed per sample, reproducibility, increased sample throughput, robust and validated statistical methodology, [and] lower IT infrastructure requirements for data handling and manipulation."

In a statement announcing the project with BGI, Pando said that Exonhit looks forward to working with the institute as a "preferred partner on future discovery projects."

Zifei Yang, director of pharma-business development at BGI, said the institute's pharmaceutical and biotech partners are "searching for prognostic and predictive biomarkers in animal models for designing clinical trials and developing companion diagnostics."

This week, Yang said that BGI is "looking for developing more trials and getting more results" with Exonhit, adding there is a "variety of scenarios where combining the two platforms would be beneficial." He did not elaborate.

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'Core Platform'

Exonhit first launched its SpliceArray platform as a service in 2005. Since then, it has evolved to include three genome-wide splice arrays for human, mouse, and rat studies.

The company also offers clients the ability to design custom arrays, which are manufactured by Affymetrix and Agilent Technologies.

The arrays incorporate a specific probe configuration that enables users to monitor RNA splice variants. The Human Genome Wide SpliceArray, for instance, monitors known and predicted alternative RNA splicing events in about 21,000 human genes, according to the company.

In a statement, Exonhit said it believes that such information is important because RNA splicing "represents a key regulatory mechanism of gene expression. Given the large contribution of splice variants to the complexity of the human transcriptome and the high density of disease-causing mutations that occur in splicing-related sequences, the monitoring of alterations in alternatively spliced transcripts represents not only a source of potential drug targets, but also a biomarker discovery engine."

Pando said that SpliceArray remains the company's "core platform" for internally and collaboratively discovering and developing novel targets, biomarkers, and molecular diagnostic products. Indeed, the firm has used the platform in collaboration with such firms as Almac Diagnostics and BioMérieux (BAN 3/9/2010).

The firm has had one direct competitor, Kentfield, Calif.-based Jivan Biologics, which has also offered a line of splice arrays in the past. Exonhit sued Jivan in 2007 for violating its IP related to the technology and won the case last year, when the US District Court for the District of Northern California enjoined Jivan from selling splice arrays (BAN 10/27/2009). The firm currently advertises sequence capture arrays on its website, though some links refer visitors to its splice array products. An e-mail to the firm seeking comment was not returned.

Exonhit also has its own pipeline of tests and therapeutics. The firm's flagship diagnostic is AclarusDx, a blood test for Alzheimer’s disease that runs on Affy's GeneChip platform. The assay is based on a signature of around 130 genes, including some involved in inflammatory and immune mechanisms observed in AD.

Launching the test for research use in 2009, the company secured a CE-IVD Mark in March. Last month, it tapped Almac Diagnostics to perform the test in Europe (BAN 7/5/2011).

Pando last year said that Exonhit developed AclarusDx on the Genome-Wide SpliceArray, and that it uses an internally developed algorithm to read the signature. In addition, the test was developed in parallel with an Alzheimer's disease drug candidate called EHT 202 (BAN 2/16/2010).

As part of that development, ExonHit ran the Genome-Wide SpliceArray platform against clinical samples to develop signatures that can be used to evaluate performance and to stratify responders versus non-responders, Pando said last year.

Exonhit also said that it used SpliceArray in a phase II study of EHT 202 to determine whether patients who responded best to the candidate have a distinct blood-based expression profile. Results of that trial demonstrated that patients who responded well to EHT 202 had a different gene-expression profile from those whose condition declined, and this difference is specific to EHT 0202, the firm said.

According to Exonhit, efforts are ongoing to find a partner to continue clinically developing EHT 202.

Have topics you'd like to see covered in BioArray News? Contact the editor at jpetrone [at] genomeweb [.] com.

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