A 44 year old man has received a gene therapy treatment which hopes to alter human genetic material in vivo for the first time, according to an article published by AP News. On Monday this week, a team of healthcare professionals and researchers at UCSF Benioff Children’s Hospital Oakland treated Brian Madeux with Zinc Finger Nucleases (ZFNs), with the intention of curing his metabolic disease, Hunter Syndrome. Tests will not be able to confirm whether or not the treatment has worked for another three months, but early signs may start to show up in one.

Metabolic diseases are usually relatively rare, with less than 10,000 people worldwide currently suffering from them; unfortunately, this is in part due to the low survival rates associated with these diseases. Patients with Hunter Syndrome have been shown to lack a functional enzyme responsible for the breakdown of certain carbohydrates. Without the enzyme, the carbohydrates build up inside cells around the body, resulting in a number of health problems. Symptoms of the disease include susceptibility to infections, hearing loss, breathing problems, bowel issues, and distorted facial features, amongst others.

Currently, the main treatment for Hunter Syndrome is to replace the missing enzyme intravenously, but this is an imperfect solution. The treatments can cost between $100,000 and $400,000 a year and will not prevent the patient from suffering brain damage over time

Brian Madeux, now the first person to undergo in vivo gene editing, has been dealing with the condition his whole life. In the past, he’s had 26 different operations to combat the damage carbohydrate build up has done and last year, he almost died when he contracted bronchitis and pneumonia. If this treatment is successful, it will be unable to heal the damage already caused by the disease, but it should prevent any further degradation.

“It’s kind of humbling,” Mr. Madeux told AP. “I’m willing to take that risk. Hopefully it will help me and other people.”

The treatment involved intravenous insertion of an inactivated virus, containing two complementary ZFNs and a functional copy of the gene that is mutated in Hunter Syndrome. Each of the ZFNs can cleave a single strand of DNA at a chosen genomic locus; the functional gene can then be inserted into the double strand break and is incorporated into the cell’s genome.

“We cut your DNA, open it up, insert a gene, stitch it back up. Invisible mending,” said Dr. Sandy Macrae, President of Sangamo Therapeutics. “It becomes part of your DNA and is there for the rest of your life.”

Want to know more about ZFNs and Gene Editing? Check out our Gene Editing 101!

The viral capsules will use the circulatory system to reach the liver, where they will enter the liver cells to perform the editing. The team behind this work predict that only 1% of liver cells would need to be successfully edited to ‘cure’ Hunter Syndrome in Mr. Madeux.

As with many discussions around gene editing, concerns have been raised that the capsules may travel beyond the liver and edit other cells types, in particular germline cells which could then pass any edits onto Mr. Madeux’s future offspring. The scientists involved in the treatment are looking to reassure people about this, stating that the therapy has a built-in ‘safeguard’, when prevents it from working anywhere other than in liver cells.

There is also a potential risk of Mr. Madeux exhibiting a harmful immune response to the treatment, or from unintended edits being made which cause more harm. Some previous attempts at gene therapy have accidentally resulted in off-target editing that has lead to the development of cancer. Fortunately, in this instance, preliminary testing and research appeared to confirm that the treatment was safe in animals; it was these early results that caused a National Institutes of Health panel to approve this treatment.

“So far there’s been no evidence that this is going to be dangerous,” said Dr. Howard Kaufman, one of the scientists on the panel. “Now is not the time to get scared.”

This isn’t the first gene therapy to involve editing human cells; recently approved CAR-T anti-cancer therapies depend on human gene editing to redirect immune cells to attack diseased tissues. Unfortunately, these types of therapies, which involve removing cells from a patient, editing them, then reinserting them, are unsuitable for all diseases and do not always result in permanent changes. Mr. Madeux’s treatment, as an example of in vivo editing, is the first of its kind.

“I’m nervous and excited,” Mr. Madeux said. “I’ve been waiting for this my whole life, something that can potentially cure me.”

Source: AP News