They have been three moms on a mission, a tireless force behind news reports this month of a promising gene therapy for boys with a brain-ravaging disorder.
The moms are sisters: Rachel Salzman of Delray Beach; Amber Salzman of Merion Station, Pa.; and Eve Salzman Lapin of Houston. During an unimaginably grim week in December 2000, they discovered that three boys in their extended family had adrenoleukodystrophy (ALD). The genetic anomaly passes silently from generation to generation until it reveals itself as this disorder, which strips away the insulating sheath around nerve fibers. Without therapy, ALD is always fatal. Perhaps you have seen the film Lorenzo's Oil — the affliction it highlights is the nightmare I refer to.
What to do? The Salzman sisters and the rest of their family rallied. They established the Stop ALD Foundation to raise money for research. They consoled other families, pored over the literature, dropped in on medical meetings and convened researchers who might assist one another. In time they saw gene therapy as their best hope.
"Everybody can do something," Eve has said since. "It's sometimes hard when you get that kind of shocking, tragic news. You can be paralyzed. But also you can be moved to action."
This month, then, came the newsmaking report in the journal Science. Investigators in Paris had treated two Spanish boys by using a disabled virus to ferry a therapeutic gene into cells carrying the ALD defect. The disorder stopped worsening, and the boys remain in good condition today, two years after the treatment. The investigators are saying they have arrested ALD, not cured it, yet the duration of effect encourages optimism. The two boys are getting on with their lives.
And so we come back to the Salzman sisters.
"Without them, this would not have been possible," says Patrick Aubourg, a pediatrician at University Paris-Descartes, a pioneer in unraveling the genetics of ALD, and the lead author on the Science paper.
Here I need to make a disclosure: I have known Amber Salzman for years, once acted as a paid consultant to her business, and occasionally work pro bono for the Stop ALD Foundation. I need also, personally, to tell something of what she, Rachel and Eve have accomplished.
To understand the frightfulness of ALD, it helps to know a bit of the pathology. The sheath around nerve fibers in the brain consists of a fatty substance called myelin. It is this sheath that facilitates conduction of electrical impulses. The initial signal of ALD — the signal that this sheath is breaking down — may be as faint as some difficulty in concentrating. It is easily misdiagnosed, sometimes as attention deficit disorder.
Without effective therapy, though, the decline is inexorable: loss of muscle control, deafness, blindness, dementia. Death comes within a few years of diagnosis. Stem-cell transplantation, if done quickly enough, can save lives but carries high risks. For boys without good donor matches, like the two Spanish boys, it is an especially poor option, if any option at all. Everybody wants more choices in therapy.
In pushing for gene therapy, it helped the Salzman sisters that they had means and connections. Amber, for instance, is a Ph.D. mathematician and business executive. An early counselor was Tachi Yamada, then her boss and the R&D chairman at Glaxo-SmithKline, one of the world's largest drug companies. (Dr. Yamada today is president of the Global Health Program at the Bill & Melinda Gates Foundation.)
But the family also had the unrelenting, unflagging resolve they took from their torment.
Jump back to 2001, just after the family has been told that three of their boys have ALD: Amber's son, age 1, and two of Eve's three sons, ages 8 and 6. Rachel's son does not.
Amber and Rachel, learning of the work of Aubourg, fly to Paris to see him. He envisions what might be called self-transplants. Remove stem cells from bone marrow; destroy the remaining, defective cells still within the marrow; put a therapeutic gene into the removed cells and infuse them back into the body so they repopulate the marrow and then give rise to specialized cells that migrate to the brain and halt progression of brain lesions. Yet the French group needs help with the viral "vector" — an innocuous virus that effectively infects cells with genes.
Soon afterward, scouting for information at a Food and Drug Administration meeting, the two sisters meet Gabor Veres, a geneticist and virologist working to make a vector of an AIDS virus rendered harmless. There are reasons to believe a gene carried by such a vector will have a stable effect. Veres agrees to talk more someday, but he must rush off to his native Hungary.
Amber tracks down his flight number. As he boards the plane, a flight attendant hands him a message. When he gets to the home of his Hungarian mother, he finds the same message. Amber has managed to come up with her phone number and an interpreter to help with the call. She also reaches Aubourg, then on a family vacation.
For both men the message is the same: You two must meet. Now! Please! Amber sets out agenda items: nonhuman primate data, small-batch vector production, and on and on.
Rachel, meanwhile, is catching a plane to Budapest. The meeting comes off there the day after her arrival, with Rachel managing the introductions.
There isn't an R&D chief in the world who isn't trying to get his people to work with such urgency.
Help for others
Over nearly a decade, the sisters have never let up — not even after it became clear that gene therapy would not come fast enough for their own family. Today, Eve's son Oliver is gone. His brain lesions had quickly spread. Her son Elliott, running short on time, went through a transplant performed without gene therapy. Owing to the graft-versus-host disease that sometimes follows a transplant, he goes about today in a wheelchair. (But then he is a young man who is going places — he competes in quiz-bowl tournaments and statewide Latin contests.) After a similar transplant, and months in a hospital, Amber's son, Spencer, is doing fine.
Today the results of the gene therapy for the two Spanish boys are being compared to what would be expected after a successful bone-marrow transplant with a good donor match. It is for the French researchers and other medical authorities to comment on how broadly gene therapy might now be used in other ALD cases. But the implications of this investigation go well beyond ALD.
Clinical setbacks at the start of this decade quickly dulled the once heady enthusiasm over gene therapy in general. Following the ALD work and a couple other recent successes for different disorders, that disillusionment is beginning to lift. "A Comeback for Gene Therapy," said a commentary accompanying the Science paper.
Indeed, the day after the paper came out, a gene-therapy company in Cambridge, Mass., Genetix Pharmaceuticals Inc., announced that it will collaborate with Aubourg and bring trials to the United States. Geert-Jan Mulder, the Genetix board chairman, plans soon to meet Amber for the first time and discuss the next steps. Of the Salzman sisters Mulder observes, "They have really helped to bring the technology to where it is now."
A mission continues
In many respects, the Salzman sisters exemplify the way so many families emerge from the shock of a dreadful diagnosis to try to save their own and lift the burden of others. A look at the Web site of the National Organization of Rare Disorders finds hundreds of patient-advocacy groups, many with their origins in these families. Their goals, command of scientific detail and access to money will vary. Yet their stories are often similar, these stories of pain, stupendous effort and charity of purpose.
As for the sisters, their mission continues.
This week Amber is off to a gene-therapy conference in Germany. Next week Rachel goes to another FDA meeting. Considering all the hopeful news of late, I recently dared to suggest that the sisterhood may be able to slow their pace. Ease off just a little?
Rachel shot back with word of a family who had just written to her. They have had two boys with ALD. One has died. The other is blind.
"Unfortunately," she said, gently reproaching me, "there is still plenty more to do."
Richard Koenig, a former St. Petersburg Times reporter, is president of Biosyntax LLC, a communications consultancy to life-sciences companies.