Sisters rally for a therapy better than Lorenzo's Oil

Posted: November 06, 2009

The busy scientist was about to leave a conference in Washington for his native Hungary when he was buttonholed by a persistent Main Line mother worried about her son's health.

Amber Salzman told him he absolutely had to meet a researcher in France who was working on the deadly brain disease that could strike her son. He said, sure, someday.

But after boarding the plane to Hungary, he got a surprise message from the flight attendant: Salzman had already set up the meeting, and the French researcher would meet him in Budapest.

That fast-track meeting, and plenty of others arranged by Salzman and her sister Rachel, eventually led to pioneering research published today in the journal Science. The authors report that a novel gene therapy seems to stop progression of ALD, the rare disease featured in the movie Lorenzo's Oil.

The study describes results from just two patients, and the therapy is not without risks. Still, other experts said it looked promising, especially for those lacking a good match for a bone-marrow transplant, the usual treatment.

And the authors agree it would not have occurred without the Salzmans, who cold-called scientists, showed up at meetings, and urged far-flung researchers and companies to collaborate.

"They never quit, the Salzman sisters," said Nathalie Cartier, a scientist at INSERM, a public research institute in Paris.

"They are like fairies," said study leader Patrick Aubourg. "They succeed with problems that we cannot resolve."

It is not uncommon for parents of sick children to set up foundations to raise money and foster research, as the Salzmans did in creating the Stop ALD Foundation. But they had added advantages.

Amber, who has a doctorate in mathematics from Bryn Mawr College and lives in Merion, was a longtime senior executive at GlaxoSmithKline. Rachel, a veterinarian living in Florida, knew her way around a scientific paper.

What they soon learned was not encouraging.

Family crisis

It began in late 2000, when a third sister, Eve Lapin of Houston, learned that her son Oliver had ALD. He had been misdiagnosed as having attention deficit disorder and then Asperger's syndrome.

An MRI finally revealed the cruel truth: There were lesions on his brain. Further tests revealed ALD - adrenoleukodystrophy, which strikes one person in 18,000. The myelin that insulated the nerve cells in his brain was deteriorating, which could lead to seizures and dementia. He had just a few years to live.

Since the disease runs in families, Lapin had her younger son screened, and Amber Salzman had her son tested as well. Their blood revealed early signs of the illness.

The two mothers learned that they were carriers for the disease. They showed no symptoms, as ALD primarily strikes males, but they had passed it on to their sons. Their sister, Rachel, the veterinarian, was not a carrier, so her children would be fine.

Amber Salzman immediately started working her contacts at Glaxo. Her then-boss, Tachi Yamada, urged her to investigate gene therapy.

Just two months after the boys' diagnoses, she and Rachel met in Paris with French scientists Aubourg and Cartier.

The scientists had been studying the disease for more than a decade, and had gotten promising results from gene therapy on lab animals. But to proceed in humans, they needed someone to make a clinical-grade "vector" - a disabled virus that would deliver corrective genes to human bone marrow cells.

That's what led the Salzmans to meet Gabor Veres, the Hungarian scientist at the Washington meeting. He worked for Cell Genesys, which could make the right kind of vector, a lentivirus, from a disabled form of HIV.

Once on the plane for Hungary, Veres was taken aback when he got the Salzmans' message from the flight attendant. He was even more surprised when he drove to his parents' home, two hours from Budapest, where another message awaited him.

The persistent sisters had called his non-English-speaking parents, with the help of a translation service. Veres was to meet with Aubourg, the French scientist, the next day in a Budapest hotel. Rachel Salzman flew from the United States to join them. "They played a huge role to get the right people together," Veres said of the Salzmans.

Helping others

Amber Salzman soon realized that gene therapy would not come to fruition soon enough for her son or nephews.

It was also too late for Lorenzo's Oil, the treatment shown in the movie, which can reduce or delay symptoms.

Amber's older nephew, Oliver, died in 2004 at 12.

The younger one, Elliott, and her own son, Spencer Barsh, were candidates for bone marrow stem-cell transplants, but no matches were available. Instead, in 2002, both received transplants of stem cells from umbilical-cord blood.

Today, Spencer, 9, is healthy. Elliott, 15, did not fare so well. His brain is fine, but his immune system had a negative reaction to the foreign cells. He suffers from graft-vs.-host disease and uses a wheelchair.

The advantage of gene therapy is that patients do not need to find a match for a cell transplant. Instead, the patients are their own donors. The bone-marrow stem cells are removed, so their flawed genetic recipe can be corrected; the cells are then reinserted into the patient.

These stem cells give rise to progenitor cells that yield a range of blood and immune cells - including a special kind called microglia, which travel to the brain.

Microglia respond to brain injuries like "traffic cops," said Florian Eichler, an assistant professor of neurology at Harvard Medical School.

But in patients with ALD, the microglia make a flawed version of a certain enzyme, somehow leading to deterioration of the myelin sheaths that protect nerve cells. Patients' brains also suffer from an accumulation of very-long-chain fatty acids.

With gene therapy, in theory, the microglia would make the correct enzyme. Though it was too late for their family, the Salzmans kept pursuing that route for others.

Amber and Rachel spoke with researchers and regulators; Eve Lapin cared for her children and fielded the heart-wrenching calls from parents of other ill children.

At one point, Cell Genesys shut down the business unit that was developing lentiviral vectors - the kind that would be used in the trial - deciding to focus on cancer vaccines. Veres, who worked for that unit, was laid off.

The French scientists thought that was the end of their trial.

Not the Salzmans.

"You have to be one of these people who say it will work, otherwise you won't get up in the morning," said Amber, 47, now chief executive officer of Cardiokine Inc. in Philadelphia, which develops heart medicines.

They kept calling Cell Genesys. At one point, Rachel Salzman badgered a secretary to get someone's e-mail address.

"I felt terrible," she said. "But not that terrible."

They eventually got the word: The company would still make their vector.

Stephen Sherwin, the former CEO, said the company was not paid for its efforts but went ahead because the approach seemed promising and "it was the right thing to do."

He credits the Salzmans for their determination. "They made it happen," said Sherwin, whose company has since merged with BioSante.

The two patients, 7-year-old boys from Spain, were treated in 2006 and 2007. Both had brain lesions but no serious impairment.

Their brain cells continued to deteriorate for a year, but then the disease stopped progressing. More than two years after treatment, they remain stable. Left untreated, they would surely have gotten worse, said Gihan Tennekoon, director of pediatric neurology at Children's Hospital of Philadelphia, who reviewed the paper.

"I think it's a real step forward," Tennekoon said.

One potential risk is that the patients would get leukemia as the corrective genes are inserted into the patients' chromosomes.

This happened in another trial for an immune disease. But that trial used a different kind of virus to deliver the genes; in the new study, the patients show no worrisome signs so far, said Katherine A. High, a leading gene therapy expert at Children's.

The authors thanked the Salzmans and many others in a note at the end of their paper.

The sisters are pleased but not finished. They are working to get a follow-up trial in the United States. They hope someday all newborns will be screened for the disease that struck their family so they can be diagnosed before it's too late.

In 2000, plenty of people told them their quest was a long shot.

"I have had phone calls with scientists who, believe me, have a lot more degrees than I do, who've told me, 'What you're doing is not going to work,' " said Rachel, 49. "It doesn't faze me at all."

Contact staff writer Tom Avril at 215-854-2430 or tavril@phillynews.com.

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