Amber Salzman, whose determination to find a cure for her son's rare disease led to a recently successful clinical trial using gene therapy.
Editor's Note: In the year 2000, Amber Salzman was a 39-year-old mom from Philadelphia living a normal life: working as a pharmaceutical executive, raising an infant son, and enjoying time with her family. But when tragedy struck in the form of a ticking time bomb in her son's DNA, she sprang into action. Her staggering triumphs after years of turmoil exemplify how parents today can play a crucial role in pushing science forward. This is her family's story, as told to LeapsMag's Editor-in-Chief Kira Peikoff.
For a few years, my nephew Oliver, suffered from symptoms that first appeared as attention deficit disorder and then progressed to what seemed like Asperger's, and he continued to worsen and lose abilities he once had. After repeated misdiagnoses, he was finally diagnosed at age 8 with adrenoleukodystrophy, or ALD – a degenerative brain disease that puts kids on the path toward death. We learned it was an X-linked disease, so we had to test other family members. Because Oliver had it, that meant his mother, my sister, was carrier, which meant I had a 50-50 chance of being a carrier, and if I was, then my son had a 50-50 chance of getting the bad gene.
You know how some people win prizes all the time? I don't have that kind of luck. I had a sick feeling when we drew my son's blood. It was almost late December in the year 2000. Spencer was 1 and climbing around like a monkey, starting to talk—a very rambunctious kid. He tested positive, along with Oliver's younger brother, Elliott.
"The only treatment at the time was an allogenic stem cell transplant from cord blood or bone marrow."
You can imagine the dreadful things that go through your mind. Everything was fine then, but he had a horrific chance that in about 3 or 4 years, a bomb would go off. It was so tough thinking that we were going to lose Oliver, and then Spencer and Elliott were next in line. The only treatment at the time was an allogenic stem cell transplant from cord blood or bone marrow, which required finding a perfect match in a donor and then undergoing months of excruciating treatment. The mortality rate can be as high as 40 percent. If your kid was lucky enough to find a donor, he would then be lucky to leave the hospital 100 days after a transplant with a highly fragile immune system.
At the time, I was at GlaxoSmithKline in Research and Development, so I did have a background in working with drug development and I was fortunate to report to the chairman of R&D, Tachi Yamada.
I called Tachi and said, "I need your advice, I have three or four years to find a cure. What do I do?" He did some research and said it's a monogenic disease—meaning it's caused by only one errant gene—so my best bet was gene therapy. This is an approach to treatment that involves taking a sample of the patient's own stem cells, treating them outside the body with a viral vector as a kind of Trojan Horse to deliver the corrected gene, and then infusing the solution back into the patient, in the hopes that the good gene will proliferate throughout the body and stop the disease in its tracks.
Tachi said to call his friend Jim Wilson, who was a leader in the field at UPenn.
Since I live in Philadelphia I drove to see Jim as soon as possible. What I didn't realize was how difficult a time it was. This was shortly after Jesse Gelsinger died in a clinical trial for gene therapy run by UPenn—the first death for the field—and research had abruptly stopped. But when I met with Jim, he provided a road map for what it would take to put together a gene therapy trial for ALD.
Meanwhile, in parallel, I was dealing with my son's health.
After he was diagnosed, we arranged a brain MRI to see if he had any early lesions, because the only way you can stop the disease is if you provide a bone marrow transplant before the disease evolves. Once it is in full force, you can't reverse it, like a locomotive that's gone wild.
"He didn't recover like other kids because his brain was not a normal brain; it was an ALD brain."
We found he had a brain tumor that had nothing to do with ALD. It was slow growing, and we would have never found it otherwise until it was much bigger and caused symptoms. Long story short, he ended up getting the tumor removed, and when he was healing, he didn't recover like other kids because his brain was not a normal brain; it was an ALD brain. We knew we needed a transplant soon, and the gene therapy trial was unfortunately still years away.
At the time, he was my only child, and I was thinking of having additional kids. But I didn't want to get pregnant with another ALD kid and I wanted a kid who could provide a bone marrow transplant for my son. So while my son was still OK, I went through 5 cycles of in vitro fertilization, a process in which hormone shots stimulated my ovaries to produce multiple eggs, which were then surgically extracted and fertilized in a lab with my husband's sperm. After the embryos grew in a dish for three to five days, doctors used a technique called preimplantation genetic diagnosis, screening those embryos to determine which genes they carry, in order to try to find a match for Spencer. Any embryo that had ALD, we saved for research. Any that did not have ALD but were not a match for Spencer, we put in the freezer. We didn't end up with a single one that was a match.
So he had a transplant at Duke Children's Hospital at age 2, using cord blood donated from a public bank. He had to be in the hospital a long time, infusing meds multiple times a day to prevent the donor cells from rejecting his body. We were all excited when he made it out after 100 days, but then we quickly had to go back for an infection he caught.
We were still bent on moving forward with the gene therapy trials.
Jim Wilson at Penn explained what proof of concept we needed in animals to go forward to humans, and a neurologist in Paris, Patrick Aubourg, had already done that using a vector to treat ALD mice. But he wasn't sure which vector to use in humans.
The next step was to get Patrick and a team of gene therapy experts together to talk about what they knew, and what needed to be done to get a trial started. There was a lot of talk about viral vectors. Because viruses efficiently transport their own genomes into the cells they infect, they can be useful tools for sending good genes into faulty cells. With some sophisticated tinkering, molecular biologists can neuter normally dangerous viruses to make them into delivery trucks, nothing more. The biggest challenge we faced then was: How do we get a viral vector that would be safe in humans?
Jim introduced us to Inder Verma, chair of the scientific advisory board of Cell Genesys, a gene therapy company in California that was focused on oncology. They were the closest to making a viral vector that could go into humans, based on a disabled form of HIV. When I spoke to Inder, he said, "Let's review the data, but you will need to convince the company to give you the vector." So I called the CEO and basically asked him, "Would you be willing to use the vector in this horrific disease?" I told him that our trial would be the fastest way to test their vector in humans. He said, "If you can convince my scientists this is ready to go, we will put the vector forward." Mind you, this was a multi-million-dollar commitment, pro bono.
I kept thinking every day, the clock is ticking, we've got to move quickly. But we convinced the scientists and got the vector.
Then, before we could test it, an unrelated clinical trial in gene therapy for a severe immunodeficiency disease, led to several of the kids developing leukemia in 2003. The press did a bad number and scared everyone away from the field, and the FDA put studies on hold in the U.S. That was one of those moments where I thought it was over. But we couldn't let it stop. Nothing's an obstacle, just a little bump we have to overcome.
Patrick wanted to do the study in France with the vector. This is where patient advocacy is important in providing perspective on the risks vs. benefits of undergoing an experimental treatment. What nobody seemed to realize was that the kids in the 2003 trial would have died if they were not first given the gene therapy, and luckily their leukemia was a treatable side effect.
Patrick and I refused to give up pushing for approval of the trial in France. Meanwhile, I was still at GSK, working full time, and doing this at night, nonstop. Because my day job did require travel to Europe, I would stop by Paris and meet with him. Another sister of mine who did not have any affected children was a key help and we kept everything going. You really need to continually stay engaged and press the agenda forward, since there are so many things that pop up that can derail the program.
Finally, Patrick was able to treat four boys with the donated vector. The science paper came out in 2009. It was a big deal. That's when the venture money came in—Third Rock Ventures was the first firm to put big money behind gene therapy. They did a deal with Patrick to get access to the Intellectual Property to advance the trial, brought on scientists to continue the study, and made some improvements to the vector. That's what led to the new study reported recently in the New England Journal of Medicine. Of 17 patients, 15 of them are still fine at least two years after treatment.
You know how I said we felt thrilled that my son could leave the hospital after 100 days? When doing the gene therapy treatment, the hospital stay needed is much quicker. Shortly after one kid was treated, a physician in the hospital remarked, "He is fine, he's only here because of the trial." Since you get your own cells, there is no risk of graft vs. host disease. The treatment is pretty anticlimactic: a bag of blood, intravenously infused. You can bounce back within a few weeks.
Now, a few years out, approximately 20 percent of patients' cells have been corrected—and that's enough to hold off the disease. That's what the data is showing. I was blown away when it worked in the first two patients.
The formerly struggling field is now making a dramatic comeback.
Just last month, the first two treatments involving gene therapy were approved by the FDA to treat a devastating type of leukemia in children and an aggressive blood cancer in adults.
Now I run a company, Adverum Biotechnologies, that I wish existed back when my son was diagnosed, because I want people who are like me, coming to me, saying: "I have proof of concept in an animal, I need to get a vector suitable for human trials, do the work needed to file with the FDA, and move it into humans." Our company knows how to do that and would like to work with such patient advocates.
Often parents feel daunted to partake in similar efforts, telling me, "Well, you worked in pharma." Yes, I had advantages, but if you don't take no for an answer, people will help you. Everybody is one degree of separation from people who can help them. You don't need a science or business background. Just be motivated, ask for help, and have your heart in the right place.
Having said that, I don't want to sound judgmental of families who are completely paralyzed. When you get a diagnosis that your child is dying, it is hard to get out of bed in the morning and face life. My sister at a certain point had one child dying, one in the hospital getting a transplant, and a healthy younger child. To expect someone like that to at the same time be flying to an FDA meeting, it's hard. Yet, she made critical meetings, and she and her husband graciously made themselves available to talk to parents of recently diagnosed boys. But it is really tough and my heart goes out to anyone who has to live through such devastation.
Tragically, my nephew Oliver passed away 13 years ago at age 12. My other nephew was 8 when he had a cord blood transplant; our trial wasn't available yet. He had some bad graft vs. host disease and he is now navigating life using a wheelchair, but thank goodness, it stopped the disease. He graduated Stanford a year ago and is now a sports writer for the Houston Chronicle.
As for my son, today he is 17, a precocious teenager applying to colleges. He also volunteers for an organization called the Friendship Circle, providing friends for kids with special needs. He doesn't focus on disability and accepts people for who they are – maybe he would have been like that anyway, but it's part of who he is. He lost his cousin and knows he is alive today because Oliver's diagnosis gave us a head start on his.
My son's story is a good one in that he had a successful transplant and recovered.
Once we knew he would make it and we no longer needed our next child to be a match, we had a daughter using one of our healthy IVF embryos in storage. She is 14 now, but she jokes that she is technically 17, so she should get to drive. I tell her, they don't count the years in the freezer. You have to joke about it.
I am so lucky to have two healthy kids today based on advances in science.
And I often think of Oliver. We always try to make him proud and honor his name.
[Editor's Note: This story was originally published in November 2017. We are resurfacing archive hits while our staff is on vacation.]
Salzman and her son Spencer, 17, who is now healthy.
(Courtesy of Salzman)
A recent study in The Lancet Oncology showed that AI found 20 percent more cancers on mammogram screens than radiologists alone.
Published in The Lancet Oncology, the study analyzed the scans of 80,000 Swedish women with a moderate hereditary risk of breast cancer who had undergone a mammogram between April 2021 and July 2022. Half of these scans were read by AI and then a radiologist to double-check the findings. The second group of scans was read by two researchers without the help of AI. (Currently, the standard of care across Europe is to have two radiologists analyze a scan before diagnosing a patient with breast cancer.)
The study showed that the AI group detected cancer in 6 out of every 1,000 scans, while the radiologists detected cancer in 5 per 1,000 scans. In other words, AI found 20 percent more cancers than the highly-trained radiologists.
Scientists have been using MRI images (like the ones pictured here) to train artificial intelligence to detect cancers earlier and with more accuracy. Here, MIT's AI system, MIRAI, looks for patterns in a patient's mammograms to detect breast cancer earlier than ever before. news.mit.edu
But even though the AI was better able to pinpoint cancer on an image, it doesn’t mean radiologists will soon be out of a job. Dr. Laura Heacock, a breast radiologist at NYU, said in an interview with CNN that radiologists do much more than simply screening mammograms, and that even well-trained technology can make errors. “These tools work best when paired with highly-trained radiologists who make the final call on your mammogram. Think of it as a tool like a stethoscope for a cardiologist.”
AI is still an emerging technology, but more and more doctors are using them to detect different cancers. For example, researchers at MIT have developed a program called MIRAI, which looks at patterns in patient mammograms across a series of scans and uses an algorithm to model a patient's risk of developing breast cancer over time. The program was "trained" with more than 200,000 breast imaging scans from Massachusetts General Hospital and has been tested on over 100,000 women in different hospitals across the world. According to MIT, MIRAI "has been shown to be more accurate in predicting the risk for developing breast cancer in the short term (over a 3-year period) compared to traditional tools." It has also been able to detect breast cancer up to five years before a patient receives a diagnosis.
The challenges for cancer-detecting AI tools now is not just accuracy. AI tools are also being challenged to perform consistently well across different ages, races, and breast density profiles, particularly given the increased risks that different women face. For example, Black women are 42 percent more likely than white women to die from breast cancer, despite having nearly the same rates of breast cancer as white women. Recently, an FDA-approved AI device for screening breast cancer has come under fire for wrongly detecting cancer in Black patients significantly more often than white patients.
As AI technology improves, radiologists will be able to accurately scan a more diverse set of patients at a larger volume than ever before, potentially saving more lives than ever.