Feb. 27, 2019 -- When her son was born in 2011, Nicole Henwood, MD, noticed a small, white patch of skin on his thigh. A few years later, she noticed two new, darker-colored spots. She didn’t think much about them after doctors told her there was nothing to worry about. At 6, A.J. was a smiling, energetic boy who loved to adopt animals and entertain his family with his plans to become a baseball player, wondering if he should be a pitcher or play first base.
When A.J. started school, his pediatrician noticed that his vision wasn’t quite as sharp as expected. Henwood, who lives in suburban Philadelphia, brought him to a pediatric eye doctor for what she thought was a routine evaluation for glasses. This led to an appointment with an eye cancer specialist for a concerning “freckle” on his retina. She spent the next few hours sobbing in the office after the doctor told her that the spots in his retina combined with the patches on his skin made neurofibromatosis 2 (NF2) the most likely diagnosis. Suddenly, A.J. had a crippling, rare genetic disease that would cause tumors to grow in his brain and along his nerves, and there was no cure. The disease affects 1 in 30,000 people worldwide.
“For the first month after A.J.’s diagnosis, I cried every day and could barely get myself out of bed,” says Henwood, an anesthesiologist. She and her husband, Andy, a Naval officer, said they felt lost, alone, and devastated at the thought of watching their son deteriorate in front of their eyes.
Further tests to confirm A.J.’s NF2 diagnosis showed tumors on both of his hearing nerves. He also had a benign brain tumor called a meningioma dangerously close to several blood vessels and nerves, several small tumors in his lower spine, and small tumors, called hamartomas, in both of his eyes. Though he doesn’t have symptoms from these tumors yet, it is only a matter of time before they start to cause problems. A.J.’s neurologist told Henwood and her family that the best course of action was to teach her son sign language so that he can communicate when he loses his hearing.
Beyond that, they would watch each tumor to check for growth and watch for new tumors, deciding if they needed to intervene. Currently, surgery, and in some cases radiation, are the only options to remove tumors when they cause severe symptoms. Both can cause more damage to underlying nerve and brain tissue.
With no hope for effective treatment options on the horizon, Henwood and her family decided to fight for a cure on their own.
“I just woke up one day with a fire in my belly and decided that I wasn’t going to let this happen to my son.”
Rare Diseases and Orphan Drugs
According to the National Institutes of Health (NIH), there are 7,000 known rare diseases, but only 5% have approved treatments. Because of the small number of people diagnosed with each of these conditions, drug companies have traditionally had little incentive to conduct research or develop treatments for these “orphaned” diseases. Though a rare disease is defined as one that affects less than 200,000 people in the United States, taken together, these conditions affect close to 30 million Americans and close to 350 million people worldwide. Over half of those affected are children.
In 1983, Congress approved the Orphan Drug Act (ODA) to spur development of treatments for rare diseases. It provides tax credits and 7 years of exclusive rights to market any drug the FDA approves with an “orphan” designation. Although the FDA has approved 400 treatments for rare diseases, progress toward finding cures for the 7,000 remains slow.
In the meantime, families find themselves in a race against time to protect their loved ones from the devastating effects of these diseases. Some have found that the most dependable route for discovering a treatment that may achieve orphan drug status is to fund the research and development themselves. The National Organization for Rare Disorders (NORD) reports close to 200 patient-led member organizations are actively funding research.
In her quest for answers, Henwood searched through Facebook groups devoted to supporting families with NF2. She eventually joined a group called The Science of NF2, where members shared papers detailing the latest research and cutting-edge therapies for the disease.
She learned about trials involving targeted cancer drugs, but she was drawn to research around gene therapy. The goal of most gene therapies is to insert a gene into person’s cells that can either replace a damaged gene with a healthy one or turn off a broken gene. Because NF2 is caused by damage to a single gene, Henwood hoped that this disease would be a good fit for gene therapy approaches.
Henwood learned about another doctor-mom who had raised over $1 million to fund gene therapy research for Sanfilippo syndrome, a genetic condition affecting her daughter that causes severe brain damage in childhood. Through a Facebook group for doctor-moms, Henwood contacted her. She and her husband helped Henwood set up her nonprofit, NF2 BioSolutions. Henwood and several other NF2 families have grown the nonprofit with an all-volunteer army and ambassadors worldwide to raise the funds necessary to support research and educate other NF2 families about the best options for care. They have raised more than $175,000 since 2018 with a goal of $1 million needed for studies.
Henwood eventually learned of another mom who had started the same process almost 20 years ago to help find a cure for a disease known as adrenoleukodystrophy (ALD). That mom, Amber Salzman, PhD, had been an executive in research and development at GlaxoSmithKline when her nephew was diagnosed with ALD, a brain disorder that destroys the protective sheath, called myelin, that surround parts of nerve cells.
Salzman, who went on to run a biotech company, knew of a researcher who was working on a gene therapy for some of the most problematic tumor types found in NF2 and was happy to pass on the information.
Science With Heart
For over 10 years, Gary Brenner, MD, PhD, has been working to unlock the mysteries behind Schwann cell tumors, also known as schwannomas. Schwann cells produce the myelin that insulate parts of nerve cells, but when the signal to stop replicating is lost due to genetic damage, these mutated cells can form bulky tumors around nerves. Schwannomas are responsible for the hearing loss seen in NF2. Several genetic diseases increase the chance of developing schwannomas.
Brenner sees patients at Massachusetts General Hospital's Pain Management Center. His research centers on a gene therapy that targets mutated Schwann cells and reprograms them to self-destruct, leaving the underlying nerve intact and functional. So far, his research shows encouraging results against human schwannoma cells injected in mice. The therapy has reduced the size of the tumors and improved pain without causing nerve damage. The next steps include preclinical studies to ensure safety before clinical trials to learn if the benefits extend to patients. These trials are costly, time intensive, and require a thorough understanding of the regulations around the FDA process. By some estimates it can take 10-15 years and $1 billion to develop one new medicine for human use.
When Henwood connected with Brenner, they immediately worked to accelerate the timeline to move the gene therapy to human trials. “It’s motivating to know about Henwood’s child, who’s almost the same age as my own,” Brenner says. “I can’t imagine and can’t help but feel empathy. ... There is an inequity, a lack of justice in rare diseases that don’t receive the attention due to financial reasons.”
Rare disease family foundations also often provide substantial financial and logistical support and can “hook investigators up with a tremendous amount of expertise” when it comes to navigating the regulatory process of the FDA.
Chris Coburn, chief innovation officer of Partners Healthcare System of Harvard University’s affiliate hospitals, says his office has seen a steady growth in rare disease family foundations working with Harvard researchers over the past 15-20 years. These foundations often fill in the gaps for researchers in terms of funding but also expertise, accelerating the research process and changing research priorities. He’s also seen these groups supporting early career investigators with grant funding and support.
Henwood jokes that she sometimes sees herself functioning as Brenner’s executive assistant, sending alerts when paperwork is due or informing him of documents that need to be signed to move the work along. “What NF2 BioSolutions lack right now in monetary support, we make up for in terms of expertise provided by volunteers who come from pharmaceutical industry and FDA backgrounds. They know the FDA regulatory process inside and out. Without these volunteers, I don’t know what we would do. I’ve seen some FDA consultants charge over $100,000 for advice,” Henwood says.
The Legal Frontier for Rare Disease Family Foundations
Peg Brivanlou, PhD, a partner and attorney at the law firm King & Spalding, has been representing her friend’s rare disease family foundation for a few years. She is a patent lawyer with a doctorate in microbiology. When she heard about Henwood’s foundation, she offered her services for free.
“Nicole has so much drive, energy, and passion. I can only imagine how it must be to care for a child with such a devastating illness and very little resources devoted to understanding or treating it,” Brivanlou says.
Her goals are to help Henwood evaluate intellectual property, help with regulatory questions for the clinical trial process, and find other grant sources.
She sees benefits of licensing the intellectual property in certain cases -- that is, protecting the studies, results, and research that are developed, similar to copyright protection. Doing so can give family foundations some control over the development process and royalties from future profits that can go toward continued research.
As reported by Kaiser Health News, there are instances where foundations spend years raising money, supporting early proof-of-concept work, and overcoming early regulatory hurdles only to be cut out at the end. The license for the intellectual property usually goes directly to the pharmaceutical or biotech company, taking all future decision making and any share in profits out of the hands of the families that have done the risky work of proving that the therapy option works. Henwood has seen this happen to other foundations.
In most cases, family foundations have to rely on larger pharmaceutical companies to carry out the later clinical trials because of the high cost of running these trials. They also need the pharmaceutical industry to manufacture the therapies. When drug prices are then set at astronomical amounts, it can be a shock for the foundations that helped fund the early work. Many of these foundations get no share of the profits, and parents struggle to pay for lifesaving medications for their children.
For now, Henwood says she can’t wait for the day when she has to face that hurdle. “It is definitely a huge problem, but it will be a blessing to worry about pricing the drug. It would mean that we will have raised enough money, moved the process along to clinical trials, and found a company that will be able to manufacture the therapy.”
Not Just NF2
Though Henwood’s experience has shown her how fragmented our drug development process still is, she does say that the pieces of the puzzle have been much easier to find because of trailblazers like Salzman. There have been so many people that have stepped out of their siloes to help. “Every time I have needed someone to guide me, or when I reached a potential hurdle, the people I needed with the skills to help have come out of the woodwork. And no one has asked me for a penny; they have all donated their talents to help these children. It has been humbling to see.”
Her next major goal is to raise enough money to fund a toxicology study as required by the FDA before clinical trials can begin. With adequate funding, the gene therapy could be in human trials as early as 14 months.
She has created the Ineedacure.org campaign to help raise funds and is also working with other NF organizations to advocate for increased federal funding for research.
Henwood’s determination to fight for a treatment for her son will not only benefit those with NF2. Strategies that work for one rare disease can also enhance treatments for other diseases.
In the whirlwind of a full-time job, a nonprofit foundation to run, and a mix of fundraisers, advocacy trips, and research conferences, Henwood often feels the pain of a tremendous cost. She has much less time to spend with her daughter and son.
“I wish I could spend more time with A.J. now, but I have to choose: spend time with him now and watch him suffer in a few years, or hope that I can make up the time in the future after we find a treatment. ... Right now, all he knows is that he has some spots that need to be watched and that mommy is out there fighting for him.”