Barbara Boughton

Synthetic Viral Vectors Show Promise for Mitigating Immune Response to Gene Therapy

Since the late 1990s, Charles Venditti, M.D., Ph.D., senior investigator with the National Human Genome Research Institute of the NIH, has been studying a group of rare and devastating pediatric genetic diseases called the hereditary methylmalonic acidemias (MMA). Most forms of the disease are caused by mutations in the methylmalonyl-CoA mutase (MUT) gene. Patients have metabolic instability, so even a minor infection can be lethal—and they often require liver and kidney transplants to survive.

Now, however, Venditti’s research is starting to explore other potential cures for the disease—specifically gene therapies. This research has shown real promise in the last few years with the use of new viral vectors for gene therapies that might avoid the immune response. Such immune responses can neutralize viral vectors, making the treatments ineffective, and have been roadblocks to the development of effective gene therapies. “Modulating the immune response is incredibly important for gene therapy,” Venditti says.

In a poster at this year’s annual meeting of the European Society of Gene and Cell Therapy, Venditti and colleagues presented research on MMA that highlighted two new novel vectors for delivering gene therapies, which might escape a pre-existing immune response to traditional adeno-associated viral (AAV) capsids and then allow readministration of treatment—if needed—as MMA children grow and mature.

The study used a synthetic AAV capsid, Anc80L65, developed by scientists at the Massachusetts Eye and Ear Infirmary, that is made from an ancient relative of today’s AAV serotypes. Hence, people today have low levels of pre-existing immunity to Anc80L65. The Anc80L65 vectors were compared with AAVs prepared with an AAV8 capsid, a well-studied hepatotropic serotype. Results showed that treatments with both vectors worked similarly well in mouse models of MMA. The treatment will rely upon co-administration with a synthetic viral particle (SVP) containing the immune modulator rapamycin—a technology created by Selecta Biosciences slated to be manufactured by Lonza—which can help block humoral immune responses. The SVP-rapamycin particle can inhibit IgG and T-cell immune response against the Anc80L65 capsid after administration of gene therapy. The resulting combination gene therapy product will, theoretically, correct MUT deficiency, block neutralization by anti-AAV antibodies, and mitigate T-cell responses in humans.

While current gene therapies are only administered once, these treatments may become less effective with time, particularly in children as they age. As children’s organs grow, and they experience increased cell multiplication, the percentage of cells containing life-saving gene therapy could be reduced, scientists theorize. Children may thus require re-dosing to maintain the efficacy of gene therapy treatments.

“Our studies suggest that the combination of a novel AAV capsid with effective immunomodulation will widely enable AAV gene therapy for patients with MMA, and by extension, using a similar approach, other metabolic disorders,” Venditti says of the study. He expects to see human gene therapy trials in MMA and other genetic diseases using these types of novel viral vectors within a few years.

“Current viral vectors now being used in gene therapies are very immunogenic,” adds Werner Cautreels, Ph.D., president and CEO of Selecta Biosciences. “After one systemic administration of gene therapy with current viral vectors, all patients will develop antibodies to them.” Many people also have pre-existing antibodies to current viruses now being used as vectors, he adds.

“By combining both Anc80L65 and the SVP-rapamycin particle we have the best of two worlds,” Dr. Cautreels says. “We believe we can bypass existing antibodies and prevent new antibodies from forming against the vector.”

The FDA has approved two cell-based gene therapies in the United States. Both Kymriah (tisagenlecleucel), which treats acute lymphoblastic leukemia, and Yescarta (axicabtagene ciloleucel), used for some types of B-cell lymphoma, are therapies that involve extracting a patient’s immune cells, genetically altering them to target and kill the cancer cells, and then reinfusing them into the patient. These are called ex vivo gene therapies, and since they use the body’s own cells, neutralization by the body’s immune system is not as much a concern as it is with in vivo gene therapies. In vivo gene therapies are sometimes considered “true” gene therapies, in that they involve injecting a healthy version of a gene into a patient with a gene mutation.

Only one experimental in vivo gene therapy is near approval in the U.S. Spark Therapeutics' Luxturna (voretigene neparvovec), a gene therapy for a rare type of hereditary blindness called RPE65-mediated inherited retinal dystrophy, is injected into the eye of patients with two mutations in the RPE65 gene. In October 2017, an FDA advisory committee unanimously endorsed the treatment, setting the stage for FDA approval.

Luxterna does not cause the same level of immune reaction that other gene therapies might, because it is given locally to the eye, which is an immune-privileged site, according to Donald Kohn, M.D., Ph.D., professor of pediatrics and microbiology, immunology, and molecular genetics at the David Geffen School of Medicine at the University of California-Los Angeles (UCLA). Unless there’s severe injury to the eye, the immune system does not generally launch a major attack against antigens there, he notes. Yet gene therapies given systemically or to other organs, such as the kidneys, are much more likely to prompt an immune response, he adds.

“Anywhere from one-third to two-thirds of people have pre-existing antibodies to the current viral vectors now being used in gene therapies,” Kohn says. “That’s a major problem, because in those who have antibodies, the viruses never get to the target (the cells that need the gene therapy).” Those with high levels of antibodies to viral vectors are also not eligible for human clinical trials of gene therapies, he adds.

There’s been significant interest in and research on synthetic capsids as a method of evading the immune response that occurs with gene therapies. “The Anc80L65 capsid seemed to evade the immune response in the mouse model (of the MMA trial), so it could be promising,” Kohn says. He also noted that most adult animals treated with viral vectors in gene therapy experiments retain stable levels of AAV, but pediatric patients could need additional treatments to maintain the therapeutic effect.

At the same time, treatments in animal studies don’t always hold up in humans, notes Mark Kay, M.D., Ph.D., Dennis Farrey family professor in the departments of pediatrics and genetics at Stanford University. “There is a lot of preclinical development into vectors that could potentially evade the immune response, but we have to see what happens when these treatments get to clinical trials with humans. The problem is that the immune responses that occur in animals are quite different from those that occur in humans,” he says.

Whether gene therapy using novel synthetic viral vectors to dampen the immune response would be both effective and safe in humans is a question that hasn’t been answered yet. Still, research into strategies to evade the body’s immune response to gene therapies is likely to continue, despite the challenges such research may face.

“The T-cell response in humans (which occurs after a gene therapy is injected) is not well understood and it’s difficult to study,” Dr. Kay says. “Animal models just can’t recapitulate the type of T-cell response we see in humans.” At the same time, new synthetic viral vectors that don’t promote—or that even prevent—an immune response, such as the Anc80L65 capsid and SVP-rapamycin, could be key to advancing research into gene therapy.

“It certainly seems to be a viable approach, and it should be explored further in additional research,” Dr. Kay concludes.



































































































































































