Drug development is a slow and trying journey, as Sangamo Therapeutics knows well. Founded in 1995, the Richmond, California-based company has hammered away for 22 years, trying to build a gene-editing platform that is precise, specific, and efficient.
It’s no easy task, but Sangamo’s Chief Medical Officer Edward Conner believes the burden of evidence has now been met. With the blessing of the FDA, the team has launched three new clinical trials in adult patients with hemophilia B, and Hurler and Hunter syndromes (aka MPS I & II). The first patient with Hunter syndrome was treated last week in California.
All three are known as monogenic diseases because they involve or are controlled by a single faulty gene. In patients with Hurler and Hunter syndromes, the gene codes for an enzyme that breaks down a type of carbohydrate. Patients with hemophilia B, on the other hand, are missing blood clotting factor IX. The standard approach for all three is to regularly treat patients with the missing enzyme or protein, but according to Conner, it’s a stopgap measure that doesn’t effectively penetrate the cells or the brain.
“What’s different about our in vivo approach is we’re actually introducing new DNA and integrating it permanently into a patient’s DNA and this is the first time that that’s been done,” Conner explained in a phone interview.
Sangamo makes its edits using zinc-finger nucleases (ZFNs), an alternative to the popular, yet early-stage CRISPR/Cas9 technology. ZFNs are delivered intravenously and then shuttled into the nucleus of the liver cells (hepatocytes) using adeno-associated virus (AAV)-derived vectors. All going well, the therapies will locate the right section of DNA in the cells and introduce a functioning copy of the defective gene. According to the information supplied on Clinicaltrials.gov, this approach “is expected to provide permanent, liver-specific expression” of the missing enzyme or protein, “for the lifetime” of the patient.
In Hunter syndrome, Conner said the investigators will measure levels of the toxic glycosaminoglycans (GAGs) that build up in the patient’s cells and overflow into the blood and the urine.
“Our goal is that we start to see expression of the enzyme and if we take patients off [enzyme replacement therapy] and we see that GAGs in the blood or the urine continue to drop or remain stable, it means that we’re getting sufficient expression of the enzyme.”
If successful, the studies could serve as a template for myriad other genetic disorders, ranging from cystic fibrosis to Fragile X syndrome and beyond. Sangamo has already initiated preclinical programs in sickle cell anemia, beta thalassemia, and Huntington’s disease.
Of course, with biotech, there’s always an elephant in the room. Safety. One major concern is immunogenicity — an immune reaction against the viral vector or the sections of DNA.
“To date, we haven’t seen much immunogenic potential with the zinc-finger nucleases,” Conner said, referring to the company’s earlier work editing DNA outside the body. “What typically occurs is a transient increase in some liver function tests, which is treated with steroids and tends to respond quite readily.”
According to Sangamo’s vice president of technology Edward Rebar, ZFNs may also have an intrinsic advantage over bacterially-derived platforms, such as CRISPR.
“We feel that zinc-finger nucleases are more similar to human-type sequences,” Rebar said during the call.
If the gene expression is strong and therapy is well tolerated, there’s one more hurdle that needs to be overcome. Gene editing could stop the progression of, for example, Hunter syndrome. However, it can’t reverse the damage that has already been done.
“We’re starting in adult patients because that’s the safe and appropriate thing to do,” Conner said, though he added that the team has already met with European health authorities about a move to earlier cases.
“They’ve really encouraged us to say; let’s understand what the safety profile looks like in some adult patients, but that we really need to work on getting into pediatric studies because that’s where the greatest potential benefit lies.”
Photo: a_crotty, Getty Images
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