Abstract
Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or glia. Gene therapy, in particular adeno-associated virus (AAV)-based, is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies, such as tauopathies. Employing AAV-based gene therapy to treat, in particular, genetic tauopathies has many potential therapeutic benefits, but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of tauopathies. In this Viewpoint, we briefly introduce some potentially treatable tauopathies, classify them according to their etiology, and discuss the potential advantages and possible problems of AAV-based gene therapy. Finally, we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies.
Highlights
TAU is a microtubule binding protein encoded in humans by the gene MAPT, which is alternatively spliced to produce eight isoforms, six of which are expressed in the human central nervous system (CNS)
Imbalanced or altered isoform expression alone of TAU can be causative for an ADlike form of Frontotemporal Dementia (FTD), Frontotemporal Lobar Degeneration with tauopathy (FTLD-TAU), and is observed in several FTD-associated tauopathies, i.a
We subdivide major tauopathies into either genetic diseases, in which proven inherited genetic mutations are the cause of the disease, or sporadic or idiopathic diseases, in which clear genetic causes are absent (Table 1) (For a more extensive list see Zimmer-Bensch and Zempel, 2021), and outline potential associated virus (AAV)-based gene therapy approaches
Summary
TAU is a microtubule binding protein encoded in humans by the gene MAPT, which is alternatively spliced to produce eight isoforms, six of which are expressed in the human central nervous system (CNS). Delivery of siRNA and ASOs remains challenging, and effects are limited to a few weeks or months, requiring several administrations per year Viral vectors, such as AAV, can present an optimal medium to deliver RNAi (RNA interference), and serve as a vector for gene replacement therapy with long lasting expression. Tauopathies with clear genetic causes would be prime targets for AAV-based gene therapy; similar approaches have been tested in animal models of other neurodegenerative diseases like Huntington’s disease (Franich et al, 2008), and AAV2/8 have already been used to deliver anti-TAU antibodies into the brain of P301S-tg-mice, a model of frontotemporal dementia (Ising et al, 2017). List of noteworthy examples of tauopathies with (epi)genetic etiologies or risk factors (Adapted from Zimmer-Bensch and Zempel (2021))
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