Shhhh! How Silencing Genes Could Treat Alzheimer’s

By | May 31st, 2023

Biogen is testing a new type of drug in clinical trials that shuts off tau protein production before it becomes a problem.

The brain’s neurons communicate with each other through chemical and electrical signals. But as Alzheimer’s disease develops, protein plaques and deposits buildup and kill the cells. Sticky proteins called amyloid plaques start building up between the cells. Meanwhile, tau protein tangles damage the cells from the inside. 

Newly approved Alzheimer’s drugs — Aduhelm and Leqembi — target amyloid plaques for clearance. (In February 2024, Biogen took Aduhelm off the market indefinitely.) But what if researchers could prevent these proteins from building up in the first place? Biogen is now testing out this strategy. 

Their new experimental drug BIIB080 silences the genes responsible for making tau proteins. Tau tangles can’t form because there aren’t any tau proteins around in the first place. The drug is currently entering the second phase of clinical trials. This makes it the first ‘gene silencing’ therapy for Alzheimer’s to get to this trial stage.

“While amyloid pathology appears earlier in the course of Alzheimer’s, tau pathology emerges closer to symptom onset and may be more closely correlated with cognitive decline,” a spokesperson from Biogen told Being Patient. “Therapies impacting amyloid plaques are now FDA approved, but no drugs directly targeting tau tangles are currently available.”  

What we know so far about Alzheimer’s gene therapies

BIIB080 isn’t the first crack at Alzheimer’s gene therapy for scientists. Past gene therapy trials took aim at the Alzheimer’s risk gene, APOE4.

APOE4 is a variant of a gene that makes a protein important for moving fats and cholesterol. Compared to over versions of this gene, APOE4 isn’t very good at doing its job. People who carry one or two copies of APOE4 are at a much higher risk of developing Alzheimer’s.

One failed strategy attempted to raise the levels of other APOE proteins in the brain to compensate for APOE4. Another trial is trying to “edit” the APOE4 gene, so that it carries the instructions for APOE2 instead (though this is still in the very early stages of trials).  APOE2 is a variant that is protective against Alzheimer’s. 

BIIB080 is a different kind of gene therapy. Rather than changing bits of the DNA to rewrite the gene, or pumping out protective proteins, this strategy focuses on “silencing” it, so to speak. 

How exactly does this new gene-silencing Alzheimer’s drug work?

To make tau inside of a cell, the cell first needs to “photocopy” the instructions. This set of instructions is called the messenger RNA.

BIIB080 is a drug called an antisense oligonucleotide, which means that it binds to a specific bit of messenger RNA, in this case tau instructions. When BIIB080 binds, it prevents these instructions from being used to make tau proteins, thus turning off its messaging.

So far, the evidence from a Phase 1 trial suggests this approach is relatively safe.

“The majority of adverse events were mild or moderate in severity, of which the most common were headache, back pain, and post-lumbar puncture syndrome,” a Biogen spokesperson said in a press release.

The Phase 2 trial will see whether lowering the levels of tau tangles in the brain will slow cognitive decline for people with mild cognitive impairment or early stage Alzheimer’s disease. The trial will finish in 2025. 

According to Biogen, if this drug proves successful, it could be tested as an add-on treatment to other approved anti-amyloid drugs. 

UPDATED 31 May 2023, 3:51 P.M. ET: An earlier version of this article stated that BIIB08o was the first gene therapy to enter the second phase of clinical trials. The correction now reads “This makes it the first ‘gene silencing’ therapy for Alzheimer’s to get to this trial stage.”

UPDATE: 3 March 2024, 9:27 P.M. ET. In February 2024, Biogen took Aduhelm off the market, citing financial concerns. Although the drug did receive accelerated, conditional FDA approval for the treatment of early Alzheimer’s disease in 2021, it is no longer available to new patients. The company announced it would sunset trials in May 2024 and cease supplying the drug to current patients in November 2024.

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