Enhanced life expectancy has led to a rise in aging associated disorders such as Alzheimer’s disease (AD). Two important pathological hallmarks of AD include the appearance of Beta amyloid plaques and neurofibrillary tangles (NFT) in the brain. The abnormal clustering of beta amyloid protein between neurons forms beta amyloid plaques. NFT’s occur as a result of aggregates formed by Tau, a protein molecule critical for microtubule stability and axonal transport. Both these processes lead to the disruption of neuronal communication subsequently leading to neuronal damage and loss.
While the current treatment options correct the cognitive symptoms of the disease, there is a quest to target specific underlying disease mechanisms. In a fascinating study in Science Translational Medicine, researchers DeVos et al suggest the use of an antisense oligonucleotide (ASO) to decrease the accumulation of the misfolded Tau proteins in the brain as well as to reverse the deposition of Tau in older mice.
In this paper, the authors designed an ASO that can specifically target human tau and reduce its expression. ASOs are synthetic single stranded nucleotides that bind to complementary mRNA or precursor pre-mRNA (transcript that undergoes splicing or other modifications) and consequently inhibit or reduce protein expression or modify protein function. For this study, the researchers used a transgenic PS19 mouse that expresses a mutant P301S human Tau protein responsible for the development of AD in these mice. Upon administration of a synthetic ASO targeting human Tau protein in the brains of these mice, the expression of human Tau protein was significantly reduced. Additionally, in order to determine whether treatment with ASO can be used to prevent the toxic accumulation of Tau proteins, they administered the ASO at 6 months of age and examined the levels of Tau protein in the brain at 9 months of age. Interestingly, treated mice showed significantly reduced Tau levels, suggesting the ability of the ASO to prevent Tau-associated pathology, as the mice got older. The researchers further demonstrated that NFT accumulation observed in 9 month old mice can be reversed upon ASO treatment, underscoring the therapeutic ability of these ASOs. AD progression is brought about by the propagation of Tau proteins within the brain. This ability of pathologic Tau to misfold naïve Tau was also reduced upon treatment with ASO. Ultimately, treatment with the ASO increased survival of these mice without causing any decline in their ability to complete a functional task such as building a nest, which is used as a common measure of cognition, social behavior and motor capabilities in mice.
These in vivo preclinical studies were further supported by studies in non-human primates, Cynomolgus monkeys. As Tau proteins are naturally occurring within the nervous system, the researchers showed that ASO treatment reduces the endogenous Tau levels in the brain and spinal cord of these monkeys. Further, the levels of Tau within the cerebrospinal fluid (CSF) can be used as a surrogate marker of treatment efficacy as the levels of Tau in the CSF correlated directly with reduction in protein level within the brain of ASO-treated monkeys.
A major limitation in the treatment of current Tau pathologies is the inability to reverse the damage that has already occurred by these aggregates. In this regard, one of the most remarkable features of this study is the ability of the human Tau ASO to not just prevent but also reverse the Tau pathologies observed in the PS19 mouse. The advancement to clinical trials requires further studies to establish its efficacy in clearing Tau aggregates without affecting general cognitive functions in humans. In the current study, ASO was administered by the surgical placement of an osmotic pump in the brain of mice. However, it is critical to identify feasible and safe mechanisms of delivery of ASOs to the central nervous system of patients. This has been an ongoing area of research for several neurological disorders.
ASOs have been studied extensively as therapeutic molecules for various disorders especially devastating neurodegenerative diseases such as Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS). A recent breakthrough in the ASO therapeutic field came about with the FDA approval of Biogen and Ionis pharmaceuticals’ Nusinersen, an ASO to treat SMA, a debilitating disease affecting children. An ASO (BIIB067) that disrupts the production of misfolded proteins produced by the mutant SOD1 gene in ALS is also in clinical trials. In partnership with Roche, Ionis is also conducting clinical trials with an ASO (ASO-HTT-Rx) which can reduce the levels of Huntingtin protein in Huntington’s disease.
AD is in dire need of a significant drug molecule that targets specific pathogenic activity and not just the symptoms of the disease. Unfortunately, promising candidates that prevent the formation of Beta amyloid plaques, such as Pfizer and Johnson & Jonhsons’ bapineuzumab, Eli Lilly’s solanezumab and Merck’s verubecestat have failed clinical trials. Despite these setbacks, companies continue to investigate novel therapies to fight this disease. Preclinical studies in this paper with an ASO that reduces Tau protein levels can transform Alzheimer’s therapeutic landscape.
DeVos SL et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy, Science Translational Medicine. DOI:10.1126/scitranslmed.aag0481
Edited by Isha Verma
About the author
Radhika completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.