Silencing the Tau Tangles

A groundbreaking clinical trial has introduced the first gene therapy aimed at silencing the MAPT gene, which is responsible for producing tau protein. Researchers administered an antisense oligonucleotide (a short molecule that binds to specific DNA or RNA sequences) designed to target MAPT mRNA—the essential step that translates the gene into protein. By binding to this mRNA, the oligonucleotide effectively prevents its translation into tau protein, thereby silencing the gene.

Promising results were previously observed in mice. As the study authors noted,

MAPT mRNA-targeting ASOs in a mouse model of tauopathy resulted in a 50% reduction of endogenous intracellular tau, reduced cell-to-cell spread of oligomerized tau, markedly reduced neuronal and cognitive impairments, and was not associated with adverse consequences.

Now, it’s time to explore the effects in humans.

Study Setup and Participant Details

The trial involved 46 participants, with an average age of 66, all diagnosed with mild Alzheimer's disease. These individuals were recruited from 12 centers across Canada, Finland, Germany, the United Kingdom, the Netherlands, and Sweden. Among them, 12 received a placebo, while the remaining 34 were divided into four groups to receive varying doses of the oligonucleotide. This randomized, double-blind trial ran from 2017 to 2020, with a treatment phase lasting four months, followed by an optional open-label extension that concluded in May 2022. Participants received the oligonucleotide via intrathecal injection (administered into the spinal canal) either monthly or quarterly for the highest dose. Three participants withdrew from the study—one from the placebo group and two from the treatment groups.

Safety Measures and Side Effects

Regarding safety, no severe adverse effects were reported, although it’s understandable that injections into the spinal canal might be uncomfortable. Participants experienced mild to moderate side effects, including post-procedure headaches and bruising. A few also reported mild fatigue, nausea, dizziness, and vomiting.

Promising Results

Now, for the results we’ve been eagerly awaiting:

Total tau protein levels showed significant reductions:

• At eight weeks post-final dose, reductions were approximately 30%, 40%, 49%, and 42% in the MAPTRx 10 mg, 30 mg, and 60 mg monthly, and 115 mg quarterly groups, respectively.
• The phosphorylated tau (the form that tangles) exhibited dose-dependent decreases, with mean percentage changes from baseline of approximately 35%, 44%, 52%, and 49% in the same groups.

Broadly speaking, at the most effective dose (60mg monthly), tau levels—including the problematic phosphorylated tau—decreased by roughly 50%.

However, it’s important to note that while the treatment effectively reduced tau-related markers, there was no significant improvement in participants’ cognitive, functional, psychiatric, or neurological outcomes throughout the trial. This raises questions: Does the treatment period need to be extended? Are other disease mechanisms compensating for the loss of tau? Is targeting tau alone insufficient for addressing disease progression?

As is typical for a Phase 1 trial, the sample size was limited. A Phase 2 trial involving over 700 participants is currently in progress.

In conclusion, the researchers acknowledge:

These results demonstrate that antisense-mediated suppression of tau protein synthesis in the CNS of participants with mild AD is possible and warrant further evaluation of the effect of MAPTRx on the clinical course of patients with AD and in other tauopathies.

Stay tuned for more developments.

Catherine Mummery discusses a pioneering gene silencing treatment for Alzheimer’s disease in this informative first-in-human trial.

Cath Mummery shares insights from CNS 2023, shedding light on the latest advancements in Alzheimer's research and treatment.