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OGT, Oxford GKP Developing Oligo-Based Array CGH Tests for Bowel Cancer, Learning Disabilities


In a departure from its traditional role as a licensing company, Oxford Gene Technology has been working with Oxford Genetics Knowledge Park, a government-funded think tank, to bring array comparative genomic hybridization-based diagnostic tests to cytogenetics labs in the UK.

Initially, Oxford GKP will be using the technology to study colorectal cancer and learning disabilities, OGT said.

James Clough, OGT's commercial director, told BioArray News last week that the company, which was founded to manage the patent estate of microarray pioneer Sir Edwin Southern, has been working with Oxford GKP in a focused effort to bring microarrays to the clinic.

"In [the UK's] National Health Service, people are looking at how you can use arrays, but the technique routinely used is karyotyping," Clough said, citing the rationale behind the project with Oxford GKP, one of eight similar knowledge parks set up in 2002.

"The GKPs are set up to bridge the gap between basic research and our NHS diagnostic area," Clough explained. "What this project is looking at, in terms of learning disabilities, is can you replace karyotyping with microarrays?"

"There's so much noise associated with oligos that it would be almost impossible for a diagnostics lab to follow up on every oligo that falls outside of your normal range."

The work with Oxford GKP is interesting, not only because it highlights Oxford Gene Technology's transition from a licensing company to one with an expanding product portfolio, but also because OGT is using oligonucleotides for array CGH instead of bacterial artificial chromosome clones, which are used in array CGH-based diagnostic services in the US.

"OGT has been historically a licensing company," Clough explained. "But about 18 months ago the company decided to diversify and set up a services business. The reason for doing that was really OGT's desire to move into a more product-focused area," he said.

Clough said that the project with Oxford GKP draws on the company's probe design skills and in-house inkjet in situ synthesis technology.

Specifically, OGT and Oxford GKP are working on developing tests that would aid cytogeneticists working with patients with learning disabilities and colorectal cancer.

With regards to learning disabilities, Clough said OGT is moving from a chip that solely covers chromosome 15 to a genome-wide syndrome array that would contain probes for known chromosomal locations that could aid in cytogenetics diagnostics work. The colorectal cancer work is more discovery-oriented, he said.

"Obviously there's been a lot of work done on gene-expression profiling in a whole range of cancers," Clough said last week. "The question is, 'Can you identify chromosomal changes in bowel cancer patients that are significant in terms of the patient's risk?'" he said. "What we are looking at is a different slant in the genetic information."

Oxford GKP has made it no secret that it would like to translate the research with OGT to the clinic. According to the organization's 2005 annual report, "the overall aim of [this work] is to develop and evaluate array-based comparative genomic hybridization and bring it into NHS clinical use."

Moreover, Oxford GKP said in the report that the collaboration with OGT was initiated with a "view to prototyping high-resolution oligonucleotide arrays for diagnostic use."

According to the report, in 2005 Oxford GKP and OGT had a fee-for-service arrangement, with OGT charging Oxford GKP £175 ($303) per chip. Jenny Taylor, the program director of Oxford GKP, said cost, along with the higher resolution gained by using oligos, is playing a significant role in how arrays make the jump from research to clinical usage.

"The advantages of using these microarrays include higher resolution, which is really important, and the fact that they are affordable; the cost of these tests is the NHS labs' main concern," Taylor said in a statement.

Taylor added that proof-of-principle studies have been completed to ensure the oligo arrays work, using colorectal cancer and learning disability samples with known chromosomal abnormalities.

"We now need to extend these studies," she said. Taylor could not be reached for further comment.

"Basically what we've been doing is they've provided samples where there are known abnormalities. We've done it blind and then identified those abnormalities," Clough explained.

Oligos vs. BACs

If Oxford GKP is successful, it will not be the first time array CGH has been used clinically. In the US, array CGH testing for chromosomal abnormalities can be performed at places like Signature Genomic Laboratories in Spokane, Wash., or Baylor College School of Medicine in Houston, Texas. Some, like Art Beaudet's lab at Baylor, have even initiated prenatal screening using array CGH (see BAN 11/2/2005, BAN 12/14/2005).

The key difference between those efforts and Oxford GKP's, is that Signature and Baylor use BAC clones for their arrays, rather than oligonucleotides. Many in the US array CGH community see oligonucleotides as something they would like to use in the future, but remain skeptical of their use in diagnostics.

"I think someday the technology is likely to move in that direction, but I don't see it happening in the next couple years," said Lisa Shaffer, acting CEO and lab director of Signature Genomics Laboratories. Signature uses a BAC array to diagnose chromosomal abnormalities and verifies its results with fluorescent in situ hybridization.

"I think oligos are a great research tool, but I have concerns about its use in diagnostics,". Shaffer told BioArray News this week.

"There's so much noise associated with oligos that it would be almost impossible for a diagnostics lab to follow up on every oligo that falls outside of your normal range," she said.

A key difference, though, is that Shaffer's lab identifies chromosomal abnormalities in patients that lack a diagnosis, while OGT's arrays focus on specific chromosomal regions and could be used more for validation, according to Clough.

"If you do [an experiment] genome-wide, you pick up changes where you don't expect them and that causes problems with patient management," Clough said.

Art Brothman, director of cytogenetics at University of Utah Health Sciences Center, said that he has used both oligos and BACs in the past, and that both have their advantages.

"[Oligos] certainly offer considerably higher resolutions and potential genes of interest can be identified," Brothman said this week.

"[But the] biggest advantage at present is that the number of copy number variant seen by BACs will be limited and it would thus be easier to interpret these, especially in a clinical setting," he said.

According to Oxford GKP's annual report, BAC arrays developed by the Wellcome Trust Sanger Institute were originally used in initial testing, only to be dumped by Oxford GKP after the organization determined that the resolution was not good enough for widespread use in cytogenetics labs.

Still, extensive work was done using BAC arrays. In fact, as of 2004, "the arrays have also been used as a diagnostic service," according to the organization. According to its annual report, the arrays are now being used to identify chromosomal abnormalities in karyotypically normal samples. "In this capacity the Oxford GKP is offering a diagnostic service to local clinical geneticists and support for the NHS Cytogenetics Lab, albeit in a research setting," the report stated.

However, in the end, Oxford GKP determined that the BAC arrays were "not the most suitable or diagnostically useful platform for use" in a clinical setting.

"The issue with BAC arrays is the resolution," said OGT's Clough. "[But]more research needs to be done with higher resolution on what new syndromes you discover [using oligos]."

Clough remarked that the work with Oxford GKP is an ongoing research project. For its part OGT is weighing different options for going forward with its own product development, Clough said.

"Our overall direction is the move into molecular diagnostics. That's an area where we want to bring together a number of different things, and really, the Oxford GKP [partnership] is an example of that work," Clough said.

Clough said that OGT is working with other customers in the array CGH arena, but declined to name them. He also said that IP for OGT's sample preparation methodology has been filed in the UK, and that OGT will most likely seek IP rights in Europe, Japan, and the US.

— Justin Petrone ([email protected]com)

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