AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

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

Genetic forms of tauopathies: inherited causes and implications of Alzheimer's disease-like TAU pathology in primary and secondary tauopathies

Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies