It began with an internet search.
Noam Baumatz, 44, was not overly concerned when his baby daughter Noga developed stomach problems at half a year. Though she was born prematurely and remained undersized, her development was ostensibly otherwise unimpaired. Noga is a happy and smiling child, said her father, lovingly referring to her as the bat zekunim of the Baumatz family, the daughter of their old age.
But when a biopsy came back positive with colitis when she was 10-months-old, Baumatz began scouring the internet for information and came across indications the condition could be rooted in her genes. That was the first inkling, said the acupuncturist and father of three, that “something dangerous” was afoot.
When the Tel Aviv couple’s genetic test results came back months later, Noga Baumatz became one of some 20-30 people on earth to be diagnosed with Hoyeraal-Hreidarsson syndrome, an ultra-rare genetic disease.
Life expectancy: 3-15 years.
Treatment suggestion: a bone marrow transplant to offset the fatal immunodeficiency disorder, which is characterized by bone marrow failure and a predisposition to cancer.
“And what they [the doctors] would tell us was, ‘In 10 years, we would save her’ because there are already very advanced gene therapies that simply fix the problem, simply change the DNA. It’s really science fiction,” he said.
After despairing of the bone marrow transplant (because “children don’t survive the transplantation if small and weak”), Baumatz was approached by a geneticist friend, Dr. Noam Diamant, who raised the possibility of locally producing a gene therapy — namely, using engineered viruses to change the defective mutation — tailored for Noga.
“We don’t need to wait for the pharmaceutical companies. The technology exists, we can do it here, in Israel, ourselves,” Baumatz recalled the Weizmann Institute-trained Diamant telling him.
With the possibility of a successful treatment being dangled in front of them, the Israeli couple is now crowdfunding money to find and fund a cure for their youngest daughter — now 2.5 years old — with gene therapy. They are hoping to raise $500,000 from the public to save their daughter.
In a Rehovot lab opened to produce the cure for Noga and operated by Diamant, they are racing for a groundbreaking solution, hoping to manufacture a drug that will correct the mutation of the RTEL1 gene that spawned the deadly disease.
Soon, Baumatz said, he will launch a global search for additional children with the progressive disease that he is convinced is under-diagnosed, particularly among Ashkenazi Jews and especially among the ultra-Orthodox.
“If we’re lucky, it will take a year,” he said of the process of producing the treatment and its one-time clinical administration to modify Noga’s defective DNA.
Though getting a new drug approved for use in humans can take a decade or more, they believe Noga will qualify for “compassionate use” by the Health Ministry, thus eliminating much of the bureaucratic red tape.
They just have to ensure she doesn’t get the flu first.
When doctors give up, parents step in
The Baumatzes are the Israeli counterparts of a global trend that has seen parents of children with rare genetic diseases spearhead biomedical research and clinical trials of gene therapy — initiatives that are not lucrative for pharmaceutical companies to pursue, due to the tiny pool of prospective patients.
“2016 was the year when gene therapy turned from promises to cures,” declared the MIT Technology Review in 2016.
“Last year, we wrote that 2016 was gene therapy’s most promising year,” it added a year later. “But 2017 proved to be even bigger.”
In December 2017, Luxterna, which targets a form of hereditary blindness, became “the first directly administered gene therapy approved in the US that targets a disease caused by mutations in a specific gene,” according to the FDA. Other clinical trials have successfully treated SCID, or “bubble boy” disease, sickle cell disease, and more.
Though the diseases themselves are designated as rare — in that each is reported among only a small population — thousands of rare diseases have been recorded around the world, affecting as many as 25 million people in the United States alone, according to the US Genetic and Rare Diseases Information Center.
According to Ben Gurion University’s National Knowledge Center for Rare / Orphan Diseases, there are over 60,000 Israelis suffering from one or more of an estimated 6,000 diseases designated by world health officials as rare, also known as “orphan” diseases.
“There are a ton of sick people from rare diseases. The diseases are rare, but many are sick — they are all children,” he said. “It’s a lot of children.”
The experimental procedures to treat orphan genetic diseases use engineered viruses, gutted of their pathogenic content, to modify defective mutations. In Noga Baumatz’s case, it would target a mutation of the RTEL1 gene, which preserves the length of the chromosome-protecting telemores.
Diamant’s TeloCure lab is producing several versions of engineered viruses, which will later be tested on stem cells drawn from Noga Baumatz’s blood. The virus that proves most effective will then be transplanted into mice, and — if successful — the manipulated cells will be transplanted back into Baumatz in a one-time administration that, they hope, will cure her of HHS.
In the meantime, Baumatz — who spends about half her time in the hospital, and is connected to a feeding tube — is being carefully monitored.
“During this year, we need to watch over the little one, keep her healthy, that’s the mission,” said Baumatz. “There’s not a huge amount we can do. We walk around wearing masks. She’s home, not in kindergarten, can’t be around other children. This is difficult, because she loves other children.”
An under-diagnosed condition among Ashkenazi Jews?
According to a 2014 study, one percent of Orthodox Ashkenazi Jews and 0.45% of the general Ashkenazi Jewish population are (largely unknowingly) carriers of the mutation behind HHS. Only recently, due to publicity over Noga Baumatz’s case, has the mutation been included in genetic screenings by Israeli medical providers.
“I have it, my wife, Tamar has it — this is the misfortune,” said Baumatz of the RTEL1 mutation. Though both had undergone genetic testing before, no one had been looking for the mutation at the time, largely because cases of HHS were so few and far between.
Though up to 1 in 100 Ashkenazi Jews could be carriers, “you don’t see children [with the genetic disease]. It’s strange,” said Baumatz.
The explanation for the disparity, he said, is that either fetuses with HHS overwhelmingly don’t survive to term, or that “people don’t know, you can’t see it on the child, and you don’t always do genetic testing and then he’s sick, and at some point he doesn’t survive the disease, and no one ever asked too many questions.”
Citing his own experience, Baumatz is certain the condition can be missed by parents, who believe a deadly flu, rather than an underlying genetic condition, to be the source of their child’s illness.
“I’m convinced that this is a disease that we will find more of,” he said, particularly among the ultra-Orthodox.
As they raise money to fund the treatment for Noga and wait on tenterhooks for the results, Baumatz said any other children they manage to locate around the world with HHS will be treated by them free of charge — if the cure, the stuff of “science fiction,” is successful.
For now, they wait, fully apprised of the stakes.
“The danger is that either she won’t survive the time we have or that we’ll fail… that the biology won’t allow us to do it,” he said.