Researchers have developed and tested a novel gene regulation therapy, that leverages zinc finger proteins, to treat brain disorders such as Alzheimer’s disease.
Alzheimer’s disease
Tau, a microtubule-binding protein, is a key player in Alzheimer’s disease (AD) and frontotemporal dementia. The accumulation and aggregation of this protein in the brain correlates with synaptic loss, neuronal loss and cognition decline. Mutations in the tau gene, MAPT, lead to tau aggregation and widespread neurodegeneration in patients with frontotemporal dementia. In addition, mice engineered to lack expression of MAPT have been found to be protected against β-amyloid (Aβ)–induced synaptotoxicity as well as neuronal damage and learning and memory deficits. Researchers have also found that reducing transgenic tau expression, even after tau accumulation in mouse models of tauopathy, can reverse its pathological effects. Overall, this supports the reduction of tau protein as a therapeutic approach for AD and other tauopathies.
Gene regulation therapy
While antisense oligonucleotides and anti-tau antibodies can facilitate tau protein reduction in the brain, they require chronic administrations to the patient and have limited ability to provide widespread knockdown. In this study, published in Science Advances, researchers used adeno-associated viruses (AAV) encoding zinc finger protein transcription factors (ZFP-TFs) to downregulate MAPT gene expression. The team specifically engineered the ZFP-TFs to precisely bind to sequences in the MAPT gene.
Following a single administration, researchers were able to selectively reduce tau mRNA and protein by 50-80% out to 11 months. This sustained tau lowering was achieved without detectable off-target effects and overt histopathological or molecular alterations. Unlike gene-editing approaches, which directly cut or alter the DNA, ZFP-TFs induce long-term changes in expression without altering the genetic material within the cells. In addition, tau reduction with AAV ZFP-TFs was also able to rescue neuronal damage around amyloid plaques in a mouse model of Alzheimer’s disease.
There are currently no disease-modifying therapies available for patients with Alzheimer’s disease or other tauopathies. This gene regulation therapy represents a promising highly specific and durable treatment approach for tau-related human brain diseases.
Image credit: By selvanegra – canva.com
