Game-changer: AD gene-silencing drug reduces tau by half

Alzheimer’s disease (AD) is a devastating diagnosis with minimal treatment options and poor outcomes. Currently, treatment is limited to a multidisciplinary approach to symptoms as well as pharmacotherapy that does not modify the disease. There are 50 million people worldwide with a diagnosis of dementia— the most common diagnosis being AD—and this number is expected to double every 20 years.

The pathophysiology of the disease has been poorly understood. Recent evidence from researchers at University College London suggests that hyperphosphorylated tau may play a key role in the neurodegeneration characteristic of the disease.^[]

The link between tau protein and AD

Although the pathophysiology of AD is complex, our understanding of the disease process is growing rapidly. In the past, clinical criteria were used to diagnose AD. However, recent evidence suggests that CSF biomarkers—including amyloid-β 42 (Aβ42) and tau, particularly total tau (t-tau) and phosphorylated tau181 (p-tau181)—as well as positron emission tomography (PET)-amyloid and PET-tau, can reliably be used as measures for disease progression.^[] 

BOX Tau is a microtubule-associated protein primarily expressed in neurons. In AD, hyperphosphorylated tau proteins pathologically accumulate intracellularly and create intraneuronal neurofibrillary tangles. This is associated with neurocognitive decline. 

Rodent and other animal studies have looked at the safety, efficacy, and disease correlation of silencing of tau through the MAPT gene, which codes for tau. These studies have shown promise in lowering tau and reducing neurocognitive impairments, as well as demonstrating safety with no adverse consequences.^[]

Currently, there are no available FDA-approved treatments targeting tau protein. However, two new medications were recently approved by the FDA—aducanumab and lecanemab—that target a separate process in AD: the accumulation of amyloid plaques. 

The first in-human phase 1 trial of MAPTRx

The University College London trial, led by neurologist Dr. Catherine Mummery, used the drug BIIB080 (IONIS-MAPTRx) to silence the gene MAPT.

The new gene-silencing medication is an antisense oligonucleotide that prevents the gene from being translated into tau. This phase 1 trial was the first time that a gene-silencing therapy had been used with respect to dementia.^[]

In the study, the average age of the patients was 66 years, and all of the 46 adults had mild AD. Three doses of the drug (or placebo) were administered intrathecally. The primary endpoint was safety, but the investigators also looked at the efficacy of the medication in lowering tau, as well as at the pharmacokinetics in the CNS. 

Both the placebo and the treatment groups reported mild-to-moderate side effects, including headache after lumbar puncture. However, the drug itself was well tolerated, with no serious adverse effects. 

All patients completed the treatment phase, and 90% of the patients completed the post-treatment phase. The effect shown on tau expression was promising, with a greater than 50% reduction of t-tau and p-tau in CNS after 24 weeks in the two treatment groups that received the highest doses of the medication. 

Although further studies are needed to assess the clinical correlations and disease-modification potential of the new medication, this study shows exceptional promise. 

Dr. Mummery stated that “the results are a significant step forward in demonstrating that we can successfully target tau with a gene-silencing drug to slow—or possibly even reverse—Alzheimer's disease, and other diseases caused by tau accumulation, in the future.”^[]