Two papers in Science sub-journals bring new ideas for the treatment of Alzheimer's disease

SourceMedical Cube Pro

AuthorYuan Li

Recently, the beta-amyloid antibody aducanumab developed by Biogen has been criticized by the FDA committee again.

When the mechanism is still unclear, various research and development institutions are undoubtedly "gambling" to do new drug research and development.

Regarding the pathogenesis of Alzheimer's disease, the industry generally agrees that β-amyloid and tau protein in the brain are related to the occurrence of the disease.

However, the reasons for the accumulation of these proteins and their relationship with each other are still unclear.

In addition to using traditional small molecule and antibody therapies to target harmful proteins, researchers have also turned to try to treat Alzheimer's disease from the transcription level or the gene level.

Science Advance published two related research papers in March, providing some new ideas for drug development.

Targeted gene transcription

In the first study, researchers from the Massachusetts Institute of Neurodegenerative Diseases and Sangamo Therapeutics used zinc finger protein transcription factor (ZFP-TF) to reduce the expression of the tau gene MAPT at the transcription level, saving Al Neuronal damage around amyloid plaques in a mouse model of Zheimer's disease.

Source: Science Advance

The structure of ZFP-TF is shown in the figure below.

Source: Science Advance

Using the AAV vector, after a single administration or intravenous injection in the hippocampus of mice, the drug selectively reduced tau mRNA and protein by 50% to 80%, and the tau protein continued to decrease, and no off-target effects were found.

Source: Science Advance

Previously, antisense oligonucleotide (ASO) therapy combined with tau mRNA to prevent protein translation or intravenous injection of anti-tau antibody can silence the expression of tau protein, but both methods require long-term administration to patients and are widespread The ability of gene silencing is limited.

Acts on nerve repair

The second study came from a research team at the University of Cambridge.

Source: Science Advance

Disruption of axonal transmission is a common feature of neurodegenerative diseases.

BNDF and TrkB jointly promote the transmission of axons, help mitochondria, lipids, proteins and other key elements move between neuronal cells, enabling nerve cells to communicate with other nerve cells and muscles.

Compared with individual receptors or ligands, the combined use of BDNF and TrkB replacement therapy showed higher efficacy.

Source: Science Advance

Gene therapy has been difficult to apply in Alzheimer’s disease before.

Reference materials:

[1] Is there any hope for listing? Biogen Alzheimer's monoclonal antibody aducanumab was criticized again by the FDA committee (Source: Medical Rubik's Cube info)

[2] Susanne Wegmann et al.

[3] Tasneem Z.
Khatib et al.
Receptor-ligand supplementation via a self-cleaving 2A peptide–based gene therapy promotes CNS axonal transport with functional recovery.
Science Advance (2021)