By Julia Karow
Good Start Genetics is in the midst of clinically validating its preconception genetic carrier screening test, which it plans to offer to select fertility clinics by year's end and additional ones in early 2012.
Unlike carrier tests from some competitors, Good Start's test will focus solely on a panel of genes and disorders for which testing is recommended by medical associations and societies and will use next-generation sequencing for most of the analysis. Earlier this month, the company, which raised $18 million last year (IS 9/14/2010), presented results from a technical validation of the assay at the American Society for Reproductive Medicine annual meeting (CSN 10/19/2011).
Because the test is not limited to a small number of disease-causing mutations, it will be more sensitive than targeted genotyping tests, regardless of ethnic groups, according to the firm. It will also be priced competitively with existing tests, although the exact pricing has not yet been determined.
According to CEO Don Hardison, the company's initial target market is in vitro fertilization clinics in the US, of which there are more than 460. Each year, he said, 400,000 couples visit a fertility center in the US, and most of the women take a carrier screening test, followed by testing of their partner if the results are positive.
Physicians in those clinics, he said, told the company they were most interested in those tests recommended by professional medical societies, prompting it to focus on these instead of a larger number of disorders.
Good Start's panel will screen the exons of about 15 genes involved in 22 disorders for which testing is recommended in different ethnic groups by either the American Congress of Obstetricians and Gynecologists, the American College of Medical Genetics, or several national Jewish advocacy organizations. These include cystic fibrosis; fragile X syndrome; spinal muscular atrophy; the hemoglobinopathies alpha-thalassemia, beta-thalassemia, and sickle cell disease; and a panel of diseases common in the Ashkenazi Jewish population, including familial dysautonomia, Tay-Sachs disease, Canavan disease, Bloom syndrome, Fanconi anemia C, Gaucher disease, mucolipidosis IV and Niemann-Pick type A disease.
Physicians do not need to order the entire panel but can pick and choose tests they want for a particular patient, depending on his or her ethnic background or family history. While all the genes will be captured and sequenced, the analysis and report will only be done for those ordered.
The company can easily add new content to the test as new genes and disorders are added to the professional societies' guidelines, Hardison said.
Most of the tests will be conducted by next-generation sequencing, though some diseases, for example fragile X syndrome, will involve other technologies.
The test analyzes genomic DNA from blood and uses a proprietary, patent-pending target capture method it developed in house to isolate the genes of interest. According to Greg Porreca, the company's co-founder and director of technology, the capture method has been fully automated on Tecan liquid-handling robots, allowing the company to handle large sample volumes in the future.
Following target capture, the company adds molecular barcodes to each sample and sequences a pool of samples on the Illumina HiSeq platform, of which it currently has two in its laboratory. Porreca declined to say how many samples are pooled in each run but said the assay has been designed for "pretty high-throughput scenarios."
According to Hardison, the company expects to obtain a clinical laboratory license from the state of Massachusetts in the near future, followed by CLIA certification after its test is on the market.
The data analysis platform assigns each read to the sample of origin, using the molecular barcode; performs consensus genotype calling for each sample across the full set of genes; and reports the presence of specific clinical mutations using software developed in house.
Physicians will receive a simple report that will tell them whether a patient is a carrier for a certain disease, Hardison said, although they can see the underlying mutation if they wish. The company will report no variants of unknown significance.
The test, which is expected to have a turnaround time of no more than 14 days, will be "very competitively priced" with other carrier screening tests, he said. The company expects the test to be covered by health insurance, as existing carrier screening tests are, and it will try to limit the amount a patient may have to pay out of pocket.
The main advantage of Good Start Genetics' test will be the larger number of mutations it can detect in the genes it scans, compared to more targeted tests.
For the cystic fibrosis gene, for example, the company will report on several hundred pathogenic variants, which it has determined through a "painstaking review of the literature," Hardison said, whereas other tests typically report 100 or fewer variants.
As new pathogenic variants in a gene are discovered, they can also easily be added to the analysis, which is impossible with targeted tests that focus on specific mutations, Hardison said.
"You can look at almost any disease that we are reporting on — we are going to have a deeper look into that gene." As a result, "we have a test offering that will be more clinically sensitive across all ethnic backgrounds," he said, which will be of particular interest to physicians treating patients from different ethnic groups or patients unsure about their own ethnic background.
The American College of Obstetricians and Gynecologists currently recommends cystic fibrosis screening using a 23-mutation panel, which has a detection rate of 94 percent in Ashkenazi Jews, but only 49 percent in Asian Americans. It recommends DNA sequencing of the full CFTR gene only in special situations.
Michael Alper, medical director of Boston IVF, a large fertility center with 12 locations throughout New England, and an advisor of Good Start Genetics, agreed that the company's strong suit is the large number of mutations it is able to detect, apparently at no greater cost than more targeted tests. He said that cystic fibrosis screening typically costs on the order of several hundred dollars today, depending on the company.
He also cited the fact that Good Start's test can be applied across ethnic groups as an advantage.
Good Start Genetics' test will compete not only with single-disease genetic carrier tests, but also with a growing number of carrier screening panels that test for larger numbers of disorders.
Counsyl's Universal Genetic Test, for example, which uses array-based genotyping, covers more than 100 genetic diseases and costs $349 (IS 5/18/2010). The company says its test, which is covered by many insurance plans, screens for more mutations than other carrier tests for many disorders and is therefore "applicable to all ethnic groups." For cystic fibrosis, for example, it includes 109 mutations.
Ambry Genetics' AmbryScreen, which also uses targeted genotyping, covers more than 75 disorders. The company claims it has the most sensitive carrier mutation panel for cystic fibrosis in the marketplace, with a 96-percent detection rate in Ashkenazi Jews, but still only a 49-percent detection rate in Asian Americans.
Also, GenPath Diagnostics, a division of Bio-Reference Laboratories, plans to introduce a "low-cost" genetic screening test at the National Society of Genetic Counselors meeting in San Diego this week that will screen for 150 inherited diseases "in any ethnicity," according to the company. That test will use multiple technologies, including PCR, Southern blotting, and array-based genotyping, and will be covered by insurance, the firm said.
According to Boston IVF's Alper, screening for too many conditions can become confusing for both patients and doctors. "The harder you look, the more you will likely find a genetic predisposition for disease," he said. "The question is, what to do with this information?"
Although the guidelines of the professional medical associations are "a moving target" and subject to change, he said they are unlikely to recommend testing of hundreds of genes in the future. "For that to be effective, you have to have the right infrastructure for counseling of couples who have these conditions," he said. "How far can you go without putting an enormous amount of stress on the medical system, and also on patients told that there is a condition that doesn't affect them but may possibly affect their children? I think there will always be a balance between cost-effectiveness and ability to absorb the information."
Not everyone agrees. According to Harvey Stern, director of reproductive genetics at the Genetics and IVF Institute in Fairfax, Va., and an advisor to Counsyl, the recommendations from professional organizations are "the minimal criteria for genetic screening," and centers with genetic professionals who can explain the tests results — especially the residual risk associated with negative results — are able to screen for more disorders.
Stern acknowledged that a sequencing-based approach will detect a higher percentage of mutations than a targeted mutation approach, but it will also pick up variants of unknown significance. For some diseases, like cystic fibrosis, even a handful of mutations accounts for a large percentage of carriers, so targeted screening works well in these, whereas in others diseases, many mutations have been identified each in a small percentage of patients, so sequencing would be more effective. Ideally, a screening test will identify all mutations present in 1 percent or more of cases. "Depending on the disease, one or the other approach would be superior" for that, he said.
Getting off to a Good Start…
Good Start Genetics has technically validated its test and is currently validating it clinically.
For the technical validation, results of which Porreca presented at the American Society for Reproductive Medicine annual meeting last week, the company analyzed 56 samples with 93 previously characterized mutations, all of which it was able to detect. In one sample, it also picked up a novel mutation that had not been previously characterized.
Samples analyzed included HapMap samples from different ethnic groups, samples from disease carriers and patients with known clinical mutations, and blood samples from various ethnic backgrounds.
The company is now putting the test through a series of clinical validations that involve several hundred samples. These are designed to study the test's robustness and reproducibility in a clinical setting, for example with different operators, reagent lots, and instruments, and are expected to be completed within the next month or two. They will also involve a validation of the information technology system.
Good Start Genetics plans to launch the test to a handful of fertility clinics by the end of this year, and to a larger number of clinics in early 2012.
Ultimately, it plans to offer the test to the entire OB/GYN market and is evaluating whether to offer the test outside the US. For those markets, it might partner with other companies, Hardison said.
The company has grown to more than 30 employees and recently moved into larger space in Cambridge, Mass. It is currently hiring a sales force in anticipation of the launch of its test.
While the company currently focuses on genetic carrier screening, it recognizes that its platform could also be used for other types of testing, for example in cancer. Going that route would require the firm to raise additional funding, "but it's something that strategically, we think about quite a bit," Hardison said.
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