A Genetic Revolution
New gene-editing technologies pioneered by Home laboratories bring hope to patients with incurable diseases.
When Brian Madeux gets sick, it’s not just annoying. It’s life threatening. Born with Hunter syndrome 44 years ago, Madeux faces serious health challenges because of the debilitating condition, which is caused by a missing or malfunctioning enzyme needed to break down cellular waste. A bout with bronchitis and pneumonia last year was extra worrisome because his disorder had contorted his airway, stifling his coughs. Multiple surgeries and weekly enzyme injections for the last 15 years have been only partially effective at reducing the waste buildup inside his cells.
Under the care of Paul Harmatz, M.D., a pediatric gastroenterologist at UCSF Benioff Children’s Hospital Oakland, Madeux has lived longer than most people afflicted with this disease. “I’m pretty happy I’ve gotten this far,” says Madeux. “I’ve seen a lot and done a lot.”
For decades, Madeux has hoped for a miracle—and last November, he finally got his wish, receiving a radically different treatment that is poised to revolutionize medicine. Developed by Richmond-based Sangamo Therapeutics, this gene-correcting technology could, in effect, tell his body to produce the missing enzyme on its own, as it is supposed to do. “I’ve been waiting for gene therapy my whole life—something that would basically cure me,” he says.
As the first patient to receive this in-body gene therapy treatment in a clinical trial, Madeux made a brave choice. If the procedure works, he essentially will be cured; if it fails, he may endure the unforeseen consequences of tinkering with his DNA. (Earlier gene therapy trials have caused immune system attacks and unintentionally activated cancer genes.) The procedure was deceptively simple: An IV delivered a solution bringing new DNA instructions to his liver over the course of a few hours. Yet it may take an unknown amount of time to determine whether his genes have been repaired.
If Madeux’s trial is successful, many others facing gene defects that cripple their health may also benefit from DNA-repairing technology that could change their lives. “It’s kind of humbling to be the first to test this,” says Madeux. “I’m willing to take that risk. Hopefully, it will help me and other people.”
A Defective Gene
Hunter syndrome is rare, with merely 500 cases documented in the United States. Since it is a recessive, X chromosome–linked disorder, boys inherit the malfunctioning gene, called iduronate-2-sulfatase (IDS), only from their mother. (Girls have far less risk of developing the disease because they receive an X chromosome from each parent; if one is defective, the other gene compensates.) This IDS gene provides the instructions for creating an enzyme that dismantles large sugar molecules inside cells and flushes them away. If the gene is mutated, the sugar molecules persist in the cells and wreak havoc on tissues and organs, severely impacting cognitive functioning and killing the majority of patients before the age of 20.
“Think of it this way,” says Melissa Hogan, president of the nonprofit Project Alive, which is dedicated to curing Hunter syndrome, and the mother of a 10-year-old son with the disease. “Their cells can’t take out the garbage, so they get filled up to the point where they stop functioning. The enzyme is like a garbage truck, taking away the harmful cellular waste.”
Testing the Technology
Because Hunter syndrome stems from just one genetic mutation, it is an ideal condition for testing gene-editing technology. For the past 20 years, Sangamo Therapeutics has been developing “DNA scissors” called zinc finger nuclease, or ZFN. Like the gene-editing technology CRISPR-Cas9 developed at UC Berkeley, ZFN can cut both strands of the DNA helix at a precise location and—depending on the case—insert donor DNA, which the body automatically uses to heal the cut. It’s akin to sending a microscopic surgeon into the cell. ZFN has greater gene-targeting specificity than CRISPR-Cas9, and though ZFN is still in the clinical trial stage, it shows a lot of promise.
“This technology allows us to put a new copy of a gene into a patient’s liver and have that gene be expressed so that an enzyme or factor or protein can be replaced for the rest of the patient’s life,” says Sandy Macrae, president of Sangamo Therapeutics. “If this experiment works, we will be able to treat patients with one infusion and give them a solution that lasts a lifetime.”
Hunter syndrome was also a good choice for the first clinical trial of in-body gene editing because its patients are unable to get complete symptomatic relief from the weekly enzyme injections, which are very expensive. Harmatz was part of the team that developed these life-extending injections in the early 2000s and has since tested four other enzyme treatments for disorders similar to Hunter syndrome. The injections can stave off physical decline and promote mobility, but they don’t cross the blood-brain barrier, which means that they can’t reverse or prevent any brain damage.
A Perfect Patient
Madeux—who lives near Phoenix and is engaged to a nurse whom he met while undergoing his enzyme injections at UCSF Benioff Children’s Hospital Oakland—has a form of the disease that does not affect his cognitive development, enabling him to work and enjoy an active lifestyle that includes skiing and horseback riding. Yet he has endured more than two dozen operations to treat his eyes, ears, and multiple bone and joint problems.
According to Harmatz, Madeux was perfect for the Sangamo trial. “He is willing to move into a new realm of therapy,” says Harmatz. “That takes a unique person to decide they want to be a pioneer in an area we don’t know much about yet.”
If the procedure works, the doors will open for future development of in vivo (inside the body) gene-editing treatments, which are poised to transform medicine in the next decades, particularly for children. Sangamo’s ambitious plan is to run patients through trials with three different levels of dosages of the therapy at multiple medical research sites.
The Centers for Disease Control and Prevention estimates that 3 to 4 percent of American babies are born with defects each year. Many of these could be eliminated with newborn screenings and early gene-therapy interventions like CRISPR-Cas9 and ZFN. Harmatz believes that this could be the case for young patients with Hunter syndrome in five to 10 years.
Some worry that gene-editing techniques are not safe and could have unforeseen consequences. Others are concerned that these treatments could create new classes of genetically enhanced people. However, scientists emphasize that the type of treatment being used for Madeux’s condition should not be confused with other more controversial attempts to edit genes in human embryos to prevent diseases or promote desirable traits.
In February 2017, the U.S. National Academies of Sciences, Engineering, and Medicine convened a panel of ethics experts who cautioned against using gene editing to enhance health or other physical characteristics, but ruled that certain cases of altering disease-causing defective genes could be permitted.
Biochemist and gene-editing expert Sam Sternberg coauthored the 2017 book A Crack in Creation with the cocreator of the CRISPR-Cas9 gene-editing technology, UC Berkeley Professor Jennifer Doudna. “People don’t have ethical concerns about using gene editing . . . in cell tissues that are not involved in reproduction, such that they won’t pass those on to future generations,” he says. “But for the parallel track of using gene editing in human embryos, it is far too early in the development of the technology to be dabbling in that.”
In other words, just because we can use a technology does not mean we should, and these complicated areas of science, law, and ethics deserve thoughtful discussion. In addition, evaluating each case individually—and making sure that the patients understand the risks as well as the hypothetical benefits—is key.
UC Hastings College of the Law Professor Robin Feldman, who has written articles about gene-editing technology patent law, says it is important to look at the long-term impacts of the technology.
“In general, with gene editing, we are at the dawn of a new medical technology,” she says. “We know these technologies are not perfect—that is the nature of any new breakthrough—but the question is, can we predict where other changes or imperfections might happen, and will those matter?”
A Worrisome Wait
While it seems prudent that the DNA revolution is proceeding at a cautious pace, with rigorous but slow FDA-approved trials at each step, the wait is frustrating if you’re one of the children with Hunter syndrome or their heartbroken parents. Three-year-old Noah Nguyen, for example, is an adorable, sociable toddler today, but he is already showing signs of debilitating cognitive regression—the hallmark of the disease—and his parents worry that treatment will come too late for him. In a blog post titled “Oh God, It’s Happening,” his parents write that their greatest fear is beginning to appear before their eyes. Whereas Noah used to count to 10 without effort, he now skips the number six. Once able to recall all the words to his favorite nursery rhymes, he now forgets some words.
His parents’ message is plain and direct: “We want to be happy,” they write, “but it is so hard knowing that our son is dying.”
The Nguyens are doing everything they can to raise money and build a movement to engage their community in support of kids with Hunter syndrome. “We have to be hopeful,” says Aywon Nguyen, Noah’s father. “Noah and the kids with Hunter are in the spotlight now because they are a symbol of hope; they could be saved.”
The Nguyens recently moved to the Bay Area to be near family and have Harmatz treat Noah. The boy gets the weekly enzyme injections—admittedly difficult to administer to a squirmy toddler, but effective in easing the stiffness he experienced. Noah’s movements were so restricted that he couldn’t climb a ladder and would topple over whenever he squatted. “Now, he is active, and we stretch him every day,” says Aywon.
Harmatz hopes that Noah can participate in one of the breakthrough gene therapy trials scheduled to begin this year. “Noah has a limited time span before too much neurological regression happens,” says Harmatz. “He really needs to move to a trial more quickly.”
Fortunately, the family is optimistic, with a celebrity spotlight boosting support for the clinical trials. Project Alive, the nonprofit dedicated to curing Hunter syndrome, was recently featured on TNT’s Inside the NBA with Charles Barkley and raised more than $1 million. That money will go toward the $2.5 million necessary to run the gene therapy clinical trials for toddlers at the nonprofit Nationwide Children’s Hospital in Columbus, Ohio. There are no drug companies or outside funders supporting this trial because the potential patient population is so small; families are raising the money themselves. Nationwide’s trial is different from the one done on Madeux in Oakland because doctors plan to inject a gene that can pass through to the brain to halt cognitive decline while also restoring the liver’s function.
While they reach for their goal, the Nguyen family—which now includes a healthy baby girl named Penelope—tries to savor each day with Noah and continues with his current treatment. “The enzymes have made him like a normal three-year-old boy,” says his father. “But he’s gotten to a plateau, and we don’t have much time.”
To learn more about Hunter syndrome and how to help those with the disorder, visit .
Racing Toward A Cure
Hunter Syndrome patients aren’t the only candidates for gene therapy or gene editing.
The Bay Area is a major center of the gene-therapy revolution, with several biotech companies developing treatments and running clinical trials. More than 10,000 genetic disorders are the result of mutations in single genes, making them relatively easy to correct. The editing systems, which target the smallest units of DNA or RNA in living cells, could undo these mutations and cure the diseases when researchers develop safe and effective ways to deliver them to human patients. Once corrected, mutations would not be passed on to future generations, leading to the eventual eradication of many disorders.
For example, cystic fibrosis is caused by a single gene mutation that leads to irregular mucus production in the lungs and digestive system, building up and blocking airways. The condition can be managed with various treatments, but without a cure, many patients will eventually need lung transplants. Gene-editing technology could be used in diagnosed infants to correct the mutation and allow them to live normal lives.
Other disorders being investigated for gene-editing cures, according to the U.S. National Library of Medicine, include:
> Metastatic lung cancer.
> HPV virus.
> B-cell acute lymphoblastic leukemia.
> Hypertrophic cardiomyopathy, a common heart condition that can lead to heart failure.
> Sickle cell anemia, a condition in which a genetic mutation causes deformed red blood cells, leading to vessel blockages, pain, and organ failure.
> Duchenne muscular dystrophy, a severe muscle-wasting disease.
> Beta thalassemia, an inherited blood disorder.