The calling card of Alzheimer’s disease is a buildup of misfolded amyloid protein in the brain, but many medicines struggle to penetrate the barrier protecting the mind from outside interference. A new study suggests that crossing the blood-brain barrier might not be necessary at all to clear amyloid plaques—and that a one-time gene therapy could one day prove an effective treatment for the devastating neurodegenerative disease.
In a study led by researchers at the Army Medical University in Chongqing, China, a gene for a protective protein was successfully delivered to mice, leading to reduced plaques and cognitive improvements. Unlike other gene therapy approaches for Alzheimer’s, this technique uses a standard liver-targeted vector rather than trying to get into the brain.
The results were published in Neuron on May 6.
It has long been known that a variant of the apolipoprotein E gene, known as APOE4, is associated with a higher risk of developing Alzheimer’s disease. But more recently, protective versions of the gene have also been identified, most notably a variant called APOE3 Christchurch.
APOE3Ch’s potential became more widely recognized when it was found in a woman who also had two copies of a mutated presenilin 1 gene. Mutations in the gene are known to cause early-onset Alzheimer’s disease that typically leads to cognitive impairment beginning around age 44. But because she also had two copies of APOE3Ch, she didn’t begin developing symptoms until her 70s.
“Clinical studies have shown that APOE3Ch can delay the onset age and pathological progression of [Alzheimer’s],” Dr. Zhong-Yuan Yu, one of the new study’s lead authors, told Fierce Biotech. The gene has also shown past promise in animal studies, Yu added.
To see if APOE3Ch could protect those not born with it, the researchers packaged the gene into a viral vector and injected it into male mice with the risky APOE4 variant. APOE is also expressed in the liver, and that’s where the gene therapy made its way. Treated mice showed smaller amyloid plaques, less brain inflammation and performed better in a maze-based memory test.
The findings surprised Jason Ulrich, Ph.D., a neurologist at Washington University in St. Louis, who wasn’t involved with the study.
“It is somewhat surprising to me, at least that changes in amyloid were observed using this approach,” Ulrich told Fierce. He noted that past studies have found knocking out APOE in the liver had no effect on brain amyloid, and even that expressing the bad form of APOE, APOE4, in the organ didn’t lead to more APOE crossing into the brain.
So, how is APOE3Ch in the liver having an effect? By clearing amyloid out of the blood, Yu told Fierce. The gene variant helps the liver and immune cells called monocytes remove amyloid from the blood, he said, and because the brain and the blood maintain an amyloid balance, this leads to an exodus of the disease-causing protein from the brain.
The researchers’ next plan is to test the approach in non-human primates before moving into clinical trials, Yu said.
The liver is a standard organ to target for gene therapy, and is much easier to reach than other brain-targeting approaches that have been tried for Alzheimer’s. But Ulrich said he needs more information before he will endorse a liver-targeting gene therapy for the notorious neurodegenerative disease.
“I would want to know a lot more about the mechanism,” he said. “It’s not clear from this study that APOE3Ch is special, as other APOE isoforms such as APOE2 or APOE3 ‘Jacksonville’ weren’t explored.”
