A man with Hunter syndrome in the US is the first person to receive a systemic drug that attempts to edit and correct a faulty genetic sequence.
44-year-old Brian Madeux is the first patient to be enrolled into a trial of Sangamo Therapeutics’ SB-913, which uses zinc finger nuclease (ZFN) technology to insert a corrective gene into a precise location in the DNA of liver cells.
It is “the first time that genome editing has been done inside a human body in an effort to change the DNA of a patient with a rare genetic disease”, according to doctors at UCSF Benioff Children’s Hospital Oakland, who are running the trial with Sangamo and are led by paediatric gastroenterologist Paul Harmatz.
The aim is to restore production of iduronate-2-sulfatase (IDS), an enzyme that is deficient in Hunter syndrome and as a result leads to a build-up of glycosaminoclycans that in turn cause symptoms such as hearing loss, declining heart function, an enlarged liver and spleen and joint stiffness.
The rare genetic disorder – also known as mucopolysaccharidosis type II (MPS II) – is currently treated via enzyme replacement therapy (RT) with recombinant IDS, sold by Shire as Elaprase (idursulfase), that is given as a long-term weekly infusion.
“Even with regular infusions of ERT, which has markedly improved functional health outcomes, patients endure progressive damage to heart, bones, and lungs,” said Harmatz. Many patients with MPS II die of airway obstruction, upper respiratory infection or heart failure before they reach the age of 20.”
Sangamo is hoping that SB-913 will do away with the continuous need for enzyme replacement therapy by correcting the defect in the IDS gene and allowing patients to produce the enzyme themselves. The firm’s CEO, Sandy Macrae, says the first dosing means “we are at the start of a new frontier of genomic medicine”.
The phase 1/2 CHAMPIONS trial is intending to enrol nine MPS II patients and is initially only monitoring the safety of the genome-editing therapy, but could eventually give some preliminary indications of efficacy.
The drug is given as a single intravenous infusion, with the genetic payload carried by adeno-associated virus (AAV) vectors that target the liver and – it is hoped – prevent the drug affecting cells in other parts of the body.
“The ZFNs enter the cells as inactive DNA instructions in a format designed only for liver cells to unlock,” explains Sangamo. “Once unlocked, the ZFNs then identify, bind to and cut the DNA in a specific location [and] Using the cells’ natural DNA repair processes, liver cells can then insert the corrective gene for IDS at that precise location.”
This targeted editing differs from gene therapy approaches in which genes are typically randomly inserted into the genome, which could cause unwanted effects. Sangamo has two other trials I play for its ZFN technology, targeting haemophilia B and MPS I, which is also known as Hurler or Hurler-Scheie syndrome.