Adrenoleukodystrophy Patient Perspective: Turning Despair into a Gene Therapy Breakthrough

Adrenoleukodystrophy, or ALD, is an x-linked disorder characterized by progressive neurologic deterioration due to demyelination of the cerebral white matter. The deterioration progresses relentlessly, leading to a vegetative state or death, usually within five years.

This disease was depicted in the movie Lorenzo's Oil with Nick Nolte and Susan Sarandon. I recall crying when watching the movie, but it was at the despair of people I didn't know and never thought would enter my life.

In Dec 2000 all that changed. After years of being misdiagnosed as having ADD and ADHD, my oldest nephew, Oliver, was diagnosed with ALD.

I would never be the same person again.

Given the genetic nature of the disease, family testing was done immediately and revealed that our precious 1 year old son had the defective gene, as did an additional nephew.

Exhaustive literature searching showed that not much research or therapy development occurs for a rare disease. The only therapy that existed for ALD was a stem cell transplant. This procedure requires that a matched donor be identified, and it is accompanied by very high mortality and morbidity risks. Tragically, this therapy is only effective if performed very early on in the demyelination process. It was too late for Oliver.

Since the demyelination process does not generally begin before the age of 4–5 years old, my son had a 4 year time bomb that was going to go off. My family and I knew that we had to move fast. We brainstormed approaches and targeted scientists and physicians to contact. Concurrently, I spoke to my then boss Tachi Yamada who was chairman of R&D at Glaxo SmithKline. Tachi said that gene therapy was my best bet, and he put me in touch with Jim Wilson. My nephew Oliver's diagnosis was in late December, but both Tachi and Jim made themselves available over the holiday season while they were out of their offices.

The key scientists working on ALD were Hugo Moser at Kennedy Krieger in Baltimore, who has since passed away, and Patrick Aubourg in Paris France who had postdoc'ed with Dr. Moser and cloned the ALD gene.

My husband and I visited with Dr. Moser and were told there was nothing we could do. If we were lucky our son would avoid the devastating childhood version that leads to death, and he may only end up in a wheelchair as a young adult. However, the adult version almost always leads to death as well.

We told Dr. Moser we can't “do nothing”—we were going to help develop a therapy. I told Dr. Moser I had been working in R&D for a Pharmaceutical company for almost 20 years. He gave me a sad discouraging smile.

I knew very well how long it takes to develop a therapy and the millions of dollars it costs, but we would be so focused and driven I knew we could beat the odds. We formed the Stop ALD Foundation and drove forward.

My sister, Rachel, who did not have any affected children, is trained as an equine veterinarian and has deep scientific experience. She flew to France with me to visit the ALD expert in France, Patrick Aubourg. We grilled Patrick and his colleague, Nathalie Cartier, for 6 hours in a small cold room in Paris. Patrick had been trying to combat this dreadful disease for years and has seen too many children die. He had recently turned to gene therapy as an approach and had promising proof of concept data in mice. However, as a clinical neurologist physician/scientist, he knew the daunting road ahead. He was impressed that Jim Wilson would help and embraced our efforts.

By early 2001, only months from first diagnosis, Jim helped us pull together the seminal meeting that drove the gene therapy approach forward. We invited physicians and scientists from the many disciplines that would be required to see this through—neurologists, transplanters, vectorologists, and gene therapists.

While stem cell transplants were very dangerous, they were efficacious. So we knew that “all we had to do” was fix the patients own stem cells so they would produce the ALD protein. However, to fix or transduce stem cells we were going to need a different gene therapy vector than had ever been used before. We were going to have to use an HIV based lentiviral vector for the first time in a human.

Many very prominent scientists told me this wouldn't work. This was at a low point in the evolution of gene therapy after the over hyping and optimism had passed. We were not deterred.

Getting such a vector would cost millions if it could even be done. Cell Genesys looked like they had promising work being done with lentiviral vectors. Jim connected me with a member of Cell Genesys's Board of Directors, Inder Verma, who suggested I come to Washington when there was a meeting that Cell Genesys members would be attending. My sister, Rachel, and I were told that Gabor Veres, a Hungarian scientist working at Cell Genesys, needed to see Patrick Aubourg's preclinical data to be convinced to take the next step.

Gabor was on a plane on his way to visit his mother in Hungary. We tracked her down and made use of an AT&T translator to arrange for Gabor to meet with Patrick the following day. We convinced Patrick to meet Rachel in Budapest to present the data to Gabor. Both Gabor and Patrick laugh as they recall this story.

We made the case that ALD would be the ideal disease for the first application of this platform technology. We were on our way, but we had to continue to drive the sense of urgency. I am sure that Rachel and I were accused of being stalkers behind our backs, but to our face all were very generous.

Another huge challenge emerged. As if gene therapy did not have enough problems, the French x-SCID trial reported that several of the children had come down with leukemia as a result of the gene therapy treatment. While the treatment used a different vector, the event was debilitating. Scientists and physicians were even more resistant than before about proceeding with another gene therapy trial. Cell Genesys was pulling the plug. They didn't want to use their vector to support our trial.

We needed to keep them on board. My insistence and “wont’ take no for an answer” approach took on a new level. I was throwing around terms like “don't worry—we'll find a way to indemnify the company.” I knew how much was at stake for Cell Genesys, but also knew what was at stake for ALD. We persisted.

In 2007, the first patient was enrolled.

In Nov 2009, the trial was reported in Science. Rachel and I were thanked for our efforts, but nothing beats knowing that there are 4 boys who have been treated in Paris who had no other options but to have their families watch them lose their abilities and die. The gene therapy procedure was a “breeze” compared to a traditional allogeneic transplant. Rather than months in isolation and being at great risk for infection and related complications, these boys were well within weeks.

Treating these 4 boys is only the beginning. This success has implications for ALD and many other diseases. A biotech called Bluebird Bio is now using these results to initiate another trial that will take place in the U.S. and Europe. We see a path forward for this therapy becoming standard of care.

On a personal note, the trial did not initiate in time to help our children. My son and my second oldest nephew had a stem cell transplant in 2002. They had to live on an isolated transplant unit for months where half the children on the unit passed away. My son is now a healthy and fun-loving 11 year old. My nephew's transplant stopped ALD, but he suffered from the ill effects of a donor transplant in that he had graft vs host disease (GVH) of the central nervous system (CNS) and now navigates life from a wheelchair, and is doing well as a junior in a very prestigious high school in Houston. We lost my dear nephew, Oliver, in August 2004, a year after my daughter was born on his birthday.

Now if you will indulge me while I speak before so many members of the press.

I am grateful for the coverage of this story that accompanied the Science article publication. It has served to inspire others to take action.

However, there has been coverage that was not helpful. You serve as the PubMed for the layman, and that puts you in a position of responsibility. I personally experienced the downside of unbalanced reporting. While regulatory agencies and physicians are tasked with considering both the risk and the benefit of a treatment, it is important that the general public understand this approach as well. Unfortunately, there are no magic bullets. Careful consideration and judgment is required. It must be terrifying enough for a physician to make the decision to treat the first patient with a new therapy, but having public misperceptions can only harm the decision making process. When the leukemia adverse events were reported relative to the x-SCID trial, it was not always put in context. Even when one considers the added morbidity and mortality resulting from the leukemia complications, many more of these children would have been dead without the gene therapy, had they solely been offered the traditionally available interventions. However, the ramifications of the reporting could have prevented a company like Cell Genesys from proceeding forward given the misperceptions and mistrust of gene therapy that was put out there. Thankfully, they did the right thing and 4 families have their boys alive.

Thank you.