Competing PGD Technologies Showcased at Fertility Meeting

Toronto, Canada—Preimplantation genetic diagnosis (PGD) has become a competitive field, with a great deal of money and credibility at stake. A session at the 2011 Canadian Fertility and Andrology Society meeting was dedicated to this topic. “The challenge in this field is ensuring that technologies have been fully and independently validated before they are widely implemented,” said session chair Jon Havelock, MD, Principal, Pacific Centre for Repro ductive Medicine, Vancouver, BC. “As clinicians, our obligation is not necessarily to use the latest technology but to do what’s best for our patients.”

Focus on Array Comparative Genomic Hybridization
Santiago Munné, PhD, head of Reprogenetics, Livingston, NJ, had helped to develop the first PGD test in the early 1990s. In 2001 he created Reprogenetics, the first laboratory in the United States to be accredited to perform PGD.

The work performed by Dr Munné and his team these days focuses on array comparative genomic hybridization (aCGH). This technique highlights the presence of defects such as microdeletions and duplications in the DNA and uses a standard control rather than parental DNA in the analysis.

“The advantages of aCGH are that all of the chromosomes are analyzed. It can analyze mutations, translocations, and many other types of genetic abnormalities, and you can get results in 12 to 23 hours, allowing for day 5 biopsy and day 6 transfer,” said Dr Munné. “In addition, parental DNA is not required, while it is for single nucleotide polymorphism [SNP], and the latter also requires data cleaning to arrive at the diagnosis.”

The use of aCGH covers a larger part of the genome than SNP analysis, at approximately 600 MB versus 1.5 MB for aCGH and SNP, respectively, said Dr Munné.

He noted that analysis of the parental DNA is unnecessary in many cases, because 90% of cases of an abnormal genetic complement have maternal origin, and because mitotic abnormalities do not have parental origin. In addition, aCGH can be used to analyze the genetic complement of the polar bodies, the chromosomal remains that are expelled from the oocyte after meiosis.

Dr Munné said that a recent study indicated that using aCGH with polar bodies results in only a 6% error rate (Geraedts J, et al. Hum Reprod. 2011;26: 3173-3180).

Day 5 aCGH has been used to produce a 100% rate of normal embryos from women as old as 42 years and a pregnancy rate of 82.2% in a 2010 study of 45 couples, including women whose average age was 37.7 years. Responding to a question from the audience, Dr Munné noted that the average survival rate with aCGH analysis of day 5 blastomeres is 90%.

Strength Is in Single Nucleotide Polymorphism Analysis
Matthew Rabinowitz, PhD, Principal, Gene Security Network, Redwood City, CA, described his transition from rocket scientist to expert in PGD after his sister had lost a child as a result of a severe genetic defect. In 2003, the consulting associate professor of aeronautics and astronautics at Stanford University dove into PGD and formed Gene Security Network in 2004.

The “Parental Support” technology developed by Dr Rabinowitz and others at his company analyzes genetic information from the fetus 3 days after fertilization, as well as from both parents. A blastomere is removed from each day-3 embryo and used for DNA screening using a microarray to detect SNPs. The results are available within 24 hours; hence, the healthiest embryos can be implanted in the mother 5 days after fertilization.

Citing a previous study that indicates that this method in blastocysts is as accurate as the “gold standard” of metaphase karyotyping, Dr Rabinowitz also said that his method has produced a 44.3% implantation rate and a 60.6% clinical pregnancy rate (Johnson DS, et al. Hum Reprod. 2010;25:1066-1075). These rates are slightly better than those they had achieved with day-3 embryos (at 48.6% vs 56.4%, respectively).

He cited a study he and his colleagues presented at the 2010 American Society for Reproductive Medicine annual meeting, which involved embryos from mothers aged >40 years being implanted after going through Parental Support screening and resulted in a 60.9% clinical implantation rate compared with a 47.7% rate among screened embryos from mothers aged 35 to 39 years. Therefore, the system “abrogates the effects of advanced maternal age,” Dr Rabinowitz said.

In April 2011 the company received a $2-million grant from the National Institutes of Health for a clinical trial of the Parental Support technology. The principal investigator is Ron Wapner, MD, Columbia University, and 20 centers are participating. “It’s a unique moment in medicine, and PGD is absolutely going to grow in prevalence,” concluded Dr Rabinowitz. “I think we’re heading for a very interesting 5 years.”