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Study Backs BlueGnome CGH Arrays as Screening Tool to Improve IVF Success Rates

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Using arrays to screen embryos during an in vitro fertilization cycle can improve pregnancy rates, according to a new study.

Pacific Reproductive Center, a Torrance, Calif.-based IVF clinic, blindly randomized 103 IVF cycles. In a treatment group of 55 cycles, the center used BlueGnome 24sure comparative genomic hybridization arrays to screen day-5 biopsies for aneuploid chromosomes prior to implantation of a single euploid embryo, while in a control group of 48 cycles, single embryos were selected using existing morphological scorecard approaches.

The ongoing pregnancy rate after 20 weeks was 69.1 percent in the 24sure treatment group versus 41.7 percent in the control group, leading the center to conclude that use of array CGH can provide a 65 percent increase in pregnancy rates. The study results are described in a recent paper in Molecular Cytogenetics.

In a statement this week BlueGnome CEO Nick Haan called the results "crucial evidence" that screening using 24sure arrays can improve IVF success rates, arguing that the method has the potential to become the "default standard of care for all IVF cycles worldwide."

Tony Gordon, head of business development at BlueGnome, told BioArray News that such clinical studies are "essential" if array-based aneuploidy screening is to become the standard method. "This publication is very exciting and represents an important step on the road" toward the method being proven in clinical trials, he said.

Cambridge, UK-based BlueGnome launched its research-use-only 24sure arrays three years ago. The product relies on a bacterial artificial chromosome array and software to screen for abnormal or aneuploid chromosomes (BAN 9/8/2009). A number of IVF clinics and laboratories have already adopted 24sure, including Rome-based Genoma, Livingston, NJ-based Reprogenetics, and Melbourne IVF in Australia.

Pacific Reproductive Center introduced 24sure-based screening last year (BAN 5/17/2011).

Zhihong Yang, executive director of pre-implantation genetic diagnosis laboratories at the center, said in a statement that the method has now been "proven to be the effective means to select the chromosomally normal embryos for transfer to ensure a healthy pregnancy for infertile patients." Yang did not respond to an e-mail seeking additional comment.

In the paper, Yang and fellow authors claimed that their study was the first that applied array CGH-based screening to embryos from "young, good-prognosis patients undertaking IVF for the first time."

According to Genoma Director Francesco Fiorentino, this was significant because "for years, the PGD community has focused only on couples with a specific indication for testing," such as advanced maternal age, not considering that aneuploidies may arise in any IVF patient. He said in a statement that the fact that the authors detected a 45 percent aneuploidy rate in embryos from young patients "may explain why many young women fail to achieve a pregnancy even after transfer of good quality embryos."

The authors also addressed the cost of adding array-based services, reporting in the paper that integrating array CGH into the center's clinical IVF program cost about as much as a "more limited genetic assessment" gained from five-probe fluorescence in situ hybridization — less than $3,000.

According to Gordon, due to a number of "inconclusive" clinical trials, the use of FISH in IVF clinics has been "largely discontinued." This has created an opening for arrays. The "failure of FISH-based PGD for aneuploidy trials to show any clinical benefit has created a great deal of general skepticism of PGD for aneuploidy, and hence the burden of proof for microarray-based PGD for aneuploidy to show clinical benefit has been understandably great," said Gordon.

'Niche Market'

While BlueGnome has been successful in converting a number of IVF clinics and labs to array CGH, Gordon said that the market for 24sure is in its "early stages" and that the firm is focused on supporting additional studies to validate the test.

"We believe that further clinical studies will show the value of adding this test to IVF cycles and in the longer term will lead to a significant market," said Gordon, though he stressed that IVF is still "a niche market compared to the established and much larger cytogenetics sector."

Other array companies have not yet jumped into the array-based PGD market with a competitive offering, perhaps because of its smaller scale, although other researchers have demonstrated that SNP arrays can also be used to screen biopsies for abnormalities during an IVF cycle.

In a study published last year, the Bridge Fertility Centre's Alan Handyside argued that given the extra theoretical resolution and parent-of-origin information provided by SNP-based approaches, SNP arrays may be particularly suited to certain applications such as PGD of single-gene defects or translocation chromosome imbalance combined with comprehensive detection of aneuploidy.

Handyside was appointed head of PGD at BlueGnome in 2010 (BAN 10/19/2010). He has maintained his position at the Bridge Fertility Centre while working with BlueGnome.

Gordon said that one reason other array firms may be hesitant to enter the market with their own offerings may be the "special requirements" of PGD.

"Array-based PGD protocols need to integrate [whole-genome analysis] with arrays and software, in a timescale, biopsy to result, that can sometimes require a turn-around time under 12 hours," he said. Also, results have to be "reasonably high resolution," less than 10 megabases, with "very low noise and reliable protocols." Support requirements are also "significant," he said. "Combined, these requirements are difficult to achieve."

For its part, BlueGnome is continuing to advance the 24sure technology. Gordon said that the company is currently looking into reducing the speed of its protocol, as it is "such a time-dependent application."

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