In Genome Editing Trials, The Effects Last A Lifetime

By Ed Miseta, Chief Editor, Clinical Leader

Sandy Macrae will tell you his true underlying passion does not lie in running a successful clinical trial or bringing a new medicine to market. Those are certainly goals of every pharma and bio company, and Macrae is hoping to eventually see those outcomes as well. But, as the CEO of Sangamo Therapeutics, his ultimate goal is to make a significant contribution to how the industry approaches finding cures for diseases and, at the same time, completely alter the experience of patients taking part in clinical trials.

“What we are attempting to do will hopefully bring a lifelong benefit to patients in need,” he says. “We have a great responsibility because if something is not done correctly, it can bring a lifetime of damage to those patients. For that reason, the safety of the patient is the primary concern behind everything we do. We also have to make sure, in every case, that this is absolutely the right treatment for them.”

Sangamo Therapeutics is involved in the quickly growing field of genome editing, but with a twist. The biotech is currently recruiting patients for three rare disease clinical trials: hemophilia B, Hurler syndrome (MPS I), and Hunter syndrome (MPS II), which will mark the first time a company performs genome editing in vivo. In a nutshell, the treatments will replace a patient’s defective or missing gene with a therapeutic gene that will be permanently stitched into the liver cells of the patient. 

Hope For Hemophilia Patients

One of the genome editing therapies Sangamo is perfecting will help patients with the rare blood-clotting disorder known as hemophilia B. In this case, a therapeutic gene will be delivered intravenously to enable a patient’s liver to produce normal levels of clotting factor IX, the missing or defective blood clotting protein, for the rest of the person’s life. That protein will be produced from a small percentage of edited liver cells that would normally produce albumin, the most common component of blood plasma. If successful, a patient could live his or her life without the fear of uncontrolled bleeding.

Current treatments require IV infusions of clotting factor two to three times weekly, or more frequently depending on the severity of the disease. The hope is for the new gene to allow the patient’s body to produce normal levels of clotting factor for life.

According to Macrae, the new gene will be added to a precise “safe harbor” location in the liver cell’s genome using zinc finger nucleases, a genome editing technology that has been methodically matured to mitigate any safety issues inherent in permanently changing a patient’s DNA.

“The advances that have been made in molecular biology are absolutely stunning,” says Macrae, who spent time studying the topic as a physician. “Our understanding of DNA and the role of the genome, including what it does and doesn’t do, has grown enormously in recent years. We can now sequence a patient’s DNA for less than $1,000. At one time, the big question used to be whether this was something we could do. We now know we can. Today, the question is what can we do with this information once we have it. Answering that question is what will allow us to save lives.”

There are some diseases where genetics is the cause. Certain genes are missing or a mutation will cause the disease. Sangamo can now recognize where the problems lie and go in and fix them. According to Macrae, one of his major challenges is understanding where the technology can best be used, which diseases should be addressed, and what the implications of using it might be.

Balance Risk With Benefits

For the other in vivo genome editing trials that are currently recruiting patients for Hurler and Hunter syndromes, both rare lysosomal storage disorders, Sangamo will also stitch a new copy of a gene into the liver of study volunteers with zinc finger nucleases to replace a gene that has been dysfunctional or missing since birth.

“For patients with Hurler syndrome, for instance, that missing gene results in short stature and enlarged liver and spleen,” says Macrae. “In the most severe cases, patients will die at an early age. We need to make sure the disease burden, itself, is great enough that performing this cutting-edge medical science results in the risks and benefits balancing each other out. My dream is for this technology to eventually move into diseases that are more common in patients and far less burdensome.”

The treatment’s risk lies in its mechanism of action. For most first-in-human studies, a drug is ingested by (or injected into) a patient. The concentration of the drug in the patient is monitored as it first increases and then decreases. The patient may develop a rash or some other adverse reaction. But in all cases, the drug will eventually be expelled from the body.

With Sangamo’s genome editing treatment, that is not the case. The gene is delivered via a re-engineered virus that carries it as a payload and targets the liver. Once incorporated into the liver’s DNA with the help of zinc finger nucleases, the gene goes to work to produce the enzyme the patient is missing. However, when that small amount of DNA is stitched into the genome, it is there for life.         

“If you receive a benefit from it, you will have that benefit for the rest of your life,” says Macrae. “But if it doesn’t work, or if there are negative effects that outweigh the positive, those also will be with you for life. That is a heavy responsibility all of us have to carry every single day.”

Help Patients Understand

Macrae notes another challenge faced in these types of trials is simply explaining the genome editing process to patients and caregivers in a way that enables them to understand it.

“It is important to explain what we do in simplified language without being patronizing,” says Macrae. “We have to help patients understand what we are doing and how it will impact them, so they can make an informed decision and one that is best for them and their families.” 

Phase 1 trials are generally conducted on healthy volunteers. Since these trials will check the experimental genome editing treatment for safety and efficacy, it only can be used on patients with hemophilia B, Hurler syndrome, and Hunter syndrome. When the study data is received, Macrae notes it will be shared with the FDA, and a decision will be made as to whether the evidence shows this treatment is the right one for patients. The first patients to be treated will be over the age of 18. The goal is to eventually get the treatment into younger patients, since the disease will continue to progress as they age.

For now, however, Sangamo is proceeding with caution. Preliminary work has already been done in cells, mice, and nonhuman primates. The company has received clearance from the FDA to begin clinical trials, but the company still seeks patients with a high enough disease burden to justify any potential risk. It is also working closely with the FDA and IRBs to make the study as safe as possible for patients.

“No one has ever done anything like this before,” adds Macrae. “This is a very exciting time, but it also is a moment of great responsibility. We have to make sure we get this right.”

Macrae states that the beauty of this technology is its ability to add other genes to patients in a similar manner. If successful, this will enable Sangamo’s genome editing with zinc finger nucleases to be used to treat many other genetic diseases as well. Initial study results for Sangamo’s genome editing trials could be available as soon as 2018.