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Antisense-ing Alzheimer’s

in Reporting from the Lab by

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.

Journal article:

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

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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.







Transitioning into Science Policy: In conversation with Zane Martin, Ph.D.

in Face à Face/Poli-Scie by

The process of bringing bench side discoveries to bedside not only involves the efforts of scientists and doctors, but also people who serve as a bridge among the researchers, policymakers, and the public at large. These individuals work in areas involving the policies that apply science for the benefit of society in a profession that is colloquially termed ‘Science Policy’. The science policy umbrella is diverse, ranging from scientists working in federal agencies, serving as Congressional staff, or providing science policy guidance for non-profits, academia, or industry. Duties include but aren’t limited to grant management, regulatory oversight, and science communication with policymakers and the public with the goal of progressing science. Every country that pursues scientific research with the aim of bringing the discoveries to the society has people involved in this profession. Although different governments work different, interacting with a science policy professional can always provide an idea of an alternative career for Ph.D. graduates.

Becoming a policy maker or an implementer by itself involves a lot of training (apart from bench work) and persistence. Although the internet provides a lot of resources, the best information can be obtained during a personal interaction with a professional working in this area. Serendipity created an opportunity for me to interview Dr. Zane Martin who gladly obliged to talk about her role in Science Policy and how her efforts during her graduate studies landed her some prestigious science policy fellowships.

SC: Could you tell us about your educational background?

ZM: I attended graduate school at the University of Texas Medical Branch, where I investigated drug discovery techniques for neurodegenerative diseases. While completing my Masters’ thesis in Pharmacology, I synthesized and screened a library of compounds to evaluate their prophylactic/therapeutic efficacy against amyloid-beta aggregation, one of the neuropathological hallmarks of Alzheimer’s disease (AD). Thereafter, I completed my Ph.D. dissertation in Neuroscience, investigating another therapeutic strategy based on inhibiting a cellular signalling event involved in synaptic plasticity implicated in Parkinson’s disease. Following my Ph.D., I completed a postdoctoral position at the NYS Institute for Basic Research, where I investigated potential therapeutics against tau hyperphosphorylation, another hallmark of Alzheimer’s. During my postdoc, I was awarded the Jeanne B. Kempner Postdoctoral Scholar fellowship to fund my work. Collectively from these studies, I authored several peer-reviewed publications and won travel awards to several conferences to present my work.

SC: What is your current position and what does a normal day at work look like?

ZM: I am currently completing an American Association for the Advancement of Science (AAAS) Science and Technology Policy Fellowship at the National Institutes of Health (NIH). Along with the training opportunities that I avail as a recipient of this fellowship, I work at the National Institute on Aging in the Division of Neuroscience. I am involved with the implementation of the National Alzheimer’s Project Act. I help regulate funding through both grant management and by developing resources to help progress science. Examples of resources at the NIH typically involve databases like PubMed,, and GenBank. The database I am working on is based on Alzheimer’s preclinical studies with the aim of improving science rigor to increase success in clinical trials.

SC: What motivated you to transition from laboratory science into science policy?

ZM: As an AD researcher, I was aware of the potential healthcare havoc we will experience if no treatment strategy for AD is discovered as demographic shifts increase the percentage of the population over age 65. Because of this, I developed a deep respect for the policies that help with the progression of biomedicine for the betterment of our society. The NIH is a global pillar for the worldwide coordination of scientific and healthcare related collaborations to address all global health needs. By including legislation, synergies become established to help pinpoint critical global health challenges, such as finding better treatments for diseases like AD.

SC: What were your approaches to pursue science policy? Did you exploit other resources during your Ph.D. or postdoc tenure to gain skills pertaining to your goals?

ZM: I first got involved during graduate school by participating in advocacy networks in different scientific societies. I attended advocacy meetings and volunteered to help with advocacy events. To increase experience in leadership positions, I was the president of my local Association for Women in Science (AWIS) chapter during my last two years in graduate school, where I organized several local functions and chapter meetings.

During my postdoc, I created a local science advocacy group with the American Society for Biochemistry and Molecular Biology (ASBMB). My group met with our Senator’s staff to campaign for increased biomedical funding. I also volunteered as an Alzheimer’s Congressional Team Member for the Alzheimer’s Association, where I wrote OpEds for our local paper and met with policymakers to discuss the importance of biomedical funding for Alzheimer’s research.

From volunteering at societies, I found an opportunity to become a science policy intern at the American Brain Coalition (ABC). For this internship, I participated in meetings with the Congressional Neuroscience Caucus to analyse the impact and effectiveness of the BRAIN Initiative. I wrote reports from these meetings for the ABC members, and I provided other material for the ABC website, such as creating a Capitol Hill Toolkit.

I also started a blog to practice writing for different audiences. I wrote about current policy events, such as appropriations proceedings involving biomedical funding, and legislations dealing with climate change and energy, evolution and schools, and vaccination enforcement. This blog led to a consultation gig with AAAS, where I submitted blogs about science policy topics for their MemberCenter website.

I recently completed a Mirzayan Science Policy Fellowship at the National Academy of Sciences working in the Board on Life Sciences, Division on Earth and Life Studies. I helped manage projects by organizing expert speakers, panelists and reviewers, selecting the literature to guide the attendees, participating in workshops and webinars, and co-authoring the workshop summaries.

SC: Could you share your thoughts on how can a person who has no experience in science policy transition into such a role?

ZM: First and foremost, complete a Ph.D. program. Ph.D. graduates have a greater advantage because they understand science, and they know how to think critically. Another important suggestion is to network. Volunteer for science societies and nonprofits, and ask for informational interviews from people that interest you. Don’t be shy! You’ll be amazed at how receptive people really are when you reach out. And most importantly: WRITE. Write for multiple audiences. Along with scientific manuscripts, write Letters to the Editor or OpEds for your local paper, blog, submit articles to societies and nonprofits. Finally, don’t get discouraged with rejection. The great thing about science policy is that every person takes a different path to get there. So, if one path doesn’t work, try another.

SC: What are the long-term satisfactions associated with a career in this field?

ZM: I feel more purposeful in this career trajectory. Being a bench scientist is also admirable, but working in science policy is more “big picture” with work potential having a greater impact. Overall, working for the government is highly rewarding because I am serving the society.

About Zane:

I am an AAAS S&T Policy Fellow at the National Institute on Aging – National Institutes of Health, where I help with the implementation of the National Alzheimer’s Plan. I have a Ph.D. in Neuroscience and M.S. in Pharmacology from the University of Texas Medical Branch, and received postdoctoral training at the New York State Institute for Basic Research in Developmental Disabilities. My research career focused on drug discovery strategies to combat Alzheimer’s disease and related dementias. Follow her on Twitter @ZaneMartinPhD.

About Sayantan:

I’m an IRTA postdoctoral visiting fellow at the National Institute on Aging – National Institutes of Health, Baltimore, USA. Apart from science, I invest my time in networking, writing, organizing events, and consolidating efforts to build a platform that brings together scientists and industry professionals to help spread the perception of alternate careers for life science graduates. Follow me on Twitter @ch_sayantan


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