From Madeux’s point of view, the revolutionary treatment appears anything but: It was a simple matter of getting hooked up to an IV, which delivered a gene editor into his bloodstream along with copies of a corrected gene to replace the mutation he carries that is responsible for the disorder.
hunter syndrome patients are missing the enzyme that breaks down mucopolysaccharides, chains of sugar molecules that are used to build connective tissues.
“If you think of your cell as a house, and over time, trash accumulates, this enzyme sort of helps take out the trash,” Conner said. “If you don’t have it, the trash builds up, builds up, and this happens in a lot of different tissues like the heart, like the brain.”
“As the disease progresses, there is widespread damage throughout the body, including the heart, bones, joints, respiratory system and central nervous system, leading to a shortened lifespan,” Klein wrote in an email.
There is no cure for Hunter syndrome, but it can be managed and treated with enzyme replacement therapies. Still, even patients who receive regular treatments undergo progressive damage to their heart
s, bones and lungs.
“Many patients with MPS II die of airway obstruction, upper respiratory infection or heart failure before they reach the age of 20,” said Dr. Paul Harmatz, Madeux’s doctor, principal investigator for the study of the treatment and a pediatric gastroenterologist at the ucsf benioff children’s Hospital Oakland.
Conner noted that Hunter syndrome primarily affects males: One in every 100,000 to 170,000 boys is born with this genetic disease.
“It is hard to define the number of patients affected,” Klein said. “There are hundreds of boys throughout the United States and possibly thousands in the world.” In extremely rare cases, girls may be affected.
Conner explained that “it’s also a monogenetic disease: You have a mutation in one gene.” This simplicity is helpful when testing the experimental gene therapy, he said, but there’s another good reason to target hunter syndrome: Patients are “still suffering quite a bit,” he said, Madeux among them.
Testing the gene editor
The DNA-editing technology is not the headline-grabbing CRISPR but one developed by Sangamo. It is based on naturally occurring proteins called zinc finger dna-binding proteins.
These are “what your own body uses to identify sections of DNA that need to be modified or repaired,” Conner explained. The new technology uses “zinc finger technology” to snip the DNA and stitch in the gene lacking in patients with Hunter syndrome.
The technology must be “as precise, efficient and specific as possible,” he said. “Precise meaning it only targets a unique section of DNA. We have 30,000 genes in our body, and you want to make sure you are precise in where this acts.”
The gene editor must be efficient or productive when it goes to work and specific in that “it only cuts at that site and is not editing elsewhere in the DNA,” Conner said.
The zinc finger technology is delivered by a non-replicating, non-pathogenic virus: one that doesn’t make you sick and one that is commonly used by gene therapy scientists, Conner said.
He noted that it was tested first in mice and non-human primates, and the safety of the treatment and clinical trial was vetted by the National Institutes of Health.
Harmatz said, “The infusion was on Monday. We observed Madeux for 24 hours in the hospital, and he looked fine when he left for his hotel (Tuesday). He hasn’t had any problems so far.”
One shot at success
Going forward, Harmatz said, he will be monitoring levels of enzymes in Madeux’s circulating white blood cells, and in three months, he will perform a liver biopsy to see whether the corrected gene has integrated and started producing enzymes.
“We’re very early in testing this first trial,” Harmatz said. “I’m hopeful that we’ll have some production.” Since Madeux has shown no difficulties, Harmatz believes all should continue to go well.
However, he is concerned that the dose “was not enough and it turns out to be ineffective and not a benefit to him. You have one shot, one chance to have an effective therapy.”
He explained that you can’t come back in two months with a higher dose delivered and hope you get a better response, because after the first infusion, a patient becomes immune to the virus, so it’s no longer an effective delivery system.
“People are working very hard to solve this problem,” Harmatz said. Still, in about two or three months, he and Conner should know whether the treatment worked.
Dr. Sanjeev Gupta, a professor of medicine and pathology at albert einstein college of Medicine and montefiore health system, said “this is an exciting step for a long-awaited holy grail of successful gene therapy that has lasting benefit.” Gupta, who was not involved in the study, added that whether the technology will be “effective (in the body) remains to be seen.”
Along with the difficulties related to the “viral vectors used to insert gene sequences into cells,” Gupta noted that “the biology of liver cells is such that multiple copies of any given gene may exist in a single cell. Whether these multiple gene copies could be corrected in sufficient cell numbers could be a key to treatment outcome here.
“But without studies that are carefully conducted, we would not be able to know that,” he said.
“We’re very, very excited,” Conner said. “I’m honored and humbled by Madeux’s decision to participate.”
Klein also said that “Brian Madeux is very, very brave.” Thankful to Sangamo for championing the cause, she believes this first run of gene therapy is a “leap forward.”
“It is a new world of science,” Klein said. “Someone needs to be on the front line, and Brian has rose to the occasion.”