A blood test to replace amniocentesis: Israeli startup’s safe alternative

Invasive tests such as amniocentesis and chorionic villus sampling (CVS) are considered the most reliable way to identify genetic disorders during pregnancy, but are stressful for women as they carry a certain amount of risk to the fetus. For this and other reasons, many pregnant women do not take these important tests.

Though noninvasive prenatal testing (NIPT) has been offered in recent years, this blood test is much more limited: It identifies certain chromosomal disorders and disorders of individual genes that originate from the father, but not from the mother. In addition, despite the convenience and simplicity of the test, it is still a screening tool used to predict risk – not diagnostic tests like the invasive alternatives.

A blood test that could diagnose genetic disorders in utero and be able to achieve results equal to amniocentesis is the holy grail of prenatal testing – and it could come from Israel by the end of 2024.

The new test is being developed by a Tel Aviv startup called Identifai Genetics. It is headed by Amir Beker, who holds a Ph.D. in medical physics and was one of the first graduates of the prestigious Israel Defense Forces’ Talpiot program for recruits with outstanding academic ability in the sciences and leadership potential.

Beker was given the task of converting academic research that emerged from the Tel Aviv University lab of Prof. Noam Shomron into a company that could do business in the American, European and Israel markets.

It has raised about $4.5 million in funding, including from eHealth Ventures, Bonale Foundation and Shizim Venture Studio, and received some $2 million in grants from the Israel Innovation Authority. It has undertaken, and is still carrying out, clinical trials at a number of Israeli hospitals and will soon begin U.S. trials to receive Clinical Laboratory Improvement Amendments (CLIA) certification from the federal program responsible for oversight of laboratory testing on people.

If it succeeds, the test has the potential to conquer the global noninvasive prenatal testing market, which alone has a turnover of some $4 billion annually (and rising). It could also expand into new markets of its own – because of future advances in treatments that can be given to the fetus in utero, and also due to it being available where there is otherwise no alternative but to wait and see the baby’s condition after birth.

In addition to offering peace of mind at an early stage of pregnancy (week 10), replacing invasive prenatal tests with blood tests could also have huge social importance – various communities that avoid testing during pregnancy may be less opposed to a standard blood test. Terminating a pregnancy at an early stage also becomes simpler and slightly less traumatic. The test could also help couples who live under restrictive legislation in U.S. states that allow abortion until the 15th (Florida) or 18th week (Utah) – when it is still too early to obtain amniocentesis results.

Forward-thinking

In some cases, early identification could expand the possibilities for treatment or better planning in advance of a birth. For instance, for thalassemia – a blood disorder that impairs the body’s ability to produce hemoglobin (the protein responsible to transmitting oxygen to tissues) – there’s a treatment that includes introducing healthy stem cells into the fetus’ blood system, which could improve the production of normal red blood cells.

For spinal muscular atrophy (SMA), a hereditary disease that causes muscles to weaken to the point of paralysis, a medication called Spinraza has recently been developed that can be injected into the spine, thereby increasing the gene’s ability to produce the missing neuron motor protein. This causes symptoms to appear later in life and in a milder form. Current research is trying to examine the effectiveness of the treatment in utero.

These are not common practices today, but it’s vital to be forward-thinking. “There’s extensive work underway to create DNA repair mechanisms that could work in utero, and for that reason it’s necessary to know what the genetic defect is,” Beker says.

The blood test can be helpful not only at the start of pregnancy. Women undergo numerous ultrasound examinations during pregnancy to review the organs of the fetus, in order to spot any defects and abnormal findings. If anomalies are discovered, doctors try to rule out or confirm the presence of known syndromes by identifying something that might confirm it.

However, many genetic syndromes that cause anomalies in the development of critical systems, such as the brain and nervous system, are identified only in weeks 25 through 30 – when it is no longer possible to carry out invasive genetic testing due to the risk of premature birth. Consequently, the medical team must make decisions about the fetus’ health based only on imagery, without the support of genetic information.

“A doctor at Beilinson, Dr. Yuval Gielchinsky, who performs intrauterine surgeries, told me that sometimes in a late screening it’s found that the fetus has a hiatal hernia – a morphological problem that can be repaired in utero. However, there’s a 25 percent chance it’s due to a genetic defect – but there’s no time left to do an amniocentesis,” Beker says. “This means that, today, doctors don’t have a good solution to the question of whether it’s possible to repair the problem surgically, or whether it’s a broader and more severe genetic problem. In such a case, the Identifai blood test is the solution.”

How it works

Identifai is based on groundbreaking research led by the company’s CTO, Tom Rabinowitz – at the time a doctoral student of computational genomics in Prof. Shomron’s laboratory (the latter is now the company’s chief scientist). He developed a computational-probabilistic method to distinguish between fragments of maternal DNA sequences and those originating from the fetus, in accordance with physical characteristics – for example, the size of the fragment, or the nucleotide sequences at the ends of the fragment.

How does it work? Three DNA samples are taken for each family: one from the father’s oral cavity and a blood test from the mother, from which two separate samples are taken – white blood cells that contain only her DNA, and plasma from her blood that includes a mixture of DNA fragments from the mother and the fetus.

The samples are sequenced in an external laboratory, producing data files. The company uses the mother and father’s DNA samples to identify the genome by deep sequencing the mixed DNA in the plasma. The fragments of fetal DNA are separated from the maternal fragments and “reassembled” to create the fetal genome sequence. Special algorithms developed by the company analyze the fetal DNA, compare it to that of the parents, and examine whether there are changes that might indicate a genetic disorder.

In tests carried out by the company, the results are compared to chorionic villus sampling tests (the invasive test carried out in the 11th week when there is a concern about the fetus). In cases in which the woman does not take the invasive test, the fetal genome analyzed by means of the Identifai method is compared to the infant’s genome after birth. The match so far has exceeded the required threshold for clinical accuracy. In the future, the company hopes to eliminate the need for a DNA sample from the father.

In sequence

Formerly a managing partner in the Pamot venture capital fund that backed initiatives by Weizmann Institute scientists, Beker previously founded BSP Medical. That company, based on his doctoral thesis, developed an algorithm to process ECG data and for discovering blockages in blood vessels that could lead to heart attacks. He managed and led the company to an IPO on the Tel Aviv Stock Exchange.

For the genetic sequencing tests, the company worked with, among others, Ultima Genomics. That firm was founded by another graduate of the Talpiot program, Gilad Almogy, and last year unveiled a device that enables whole genome sequencing at the cost of just $100 per person. That is one-tenth the usual cost, and its release caused prices in the field to plummet. Right now, Ultima is the only competition for the U.S. biotech firm Illumina, which performs 80 percent of the world’s sequencing. It’s a prime example of how lowering the price of sequencing enables development of new kinds of tests that until now had been financially prohibitive.

When asked what’s stopping other companies from offering the same test, Beker responds: “The test is based on a complex algorithm that we developed, and which would be difficult to replicate. It allows separation between the fetal DNA and maternal DNA, and then reconstruction of the fetal DNA sequence. We have a five-year advantage in entering the market and clinical trials – and this constitutes an obstacle for competitors. NIPT is a limited test that is expanding very slowly every year. At the moment, we’re not aware of any academic research or commercial company that has achieved anything close to what we have in the broad and precise identification of genetic defects in a blood test during pregnancy.”