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First-time ‘gene silencing’ drug for AD shows promise study suggests

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A new genetic therapy for Alzheimer’s is safe and successfully lowered levels of the harmful tau protein known to cause the disease, a new world first trial suggests.

The researchers at University College London Hospitals (UCLH) NHS Foundation Trust and UCL, say the findings “are a significant step forward” in showing it may be possible to target tau to slow, or maybe even reverse, the devastating progressive neurological condition.

The phase 1b trial represents the first time that a ‘gene silencing’ approach has been taken in dementia and Alzheimer’s.

The findings suggest scientists can change the amount of tau by silencing its gene coding with a drug called BIIB080 (MAPTRx), which is an antisense oligonucleotide (short, synthetic, chemically modified chains of nucleotides that have the potential to target any gene product of interest).

This prevents the gene being translated into the protein in a doseable, reversible way. This can then lower the production of that protein and alter the course of disease.

Consultant neurologist Dr Catherine Mummery at the National Hospital for Neurology and Neurosurgery, who led the trial, said: “We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations.

“But the results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow – or possibly even reverse – Alzheimer’s disease, and other diseases caused by tau accumulation in the future.”

Further trials will be needed in larger groups of patients to determine whether this then leads to clinical benefit, but the phase 1 results published in the journal Nature Medicine are the first indication that this method has a biological effect.

There are currently no treatments targeting tau. The drugs aducanumab and lecanemab – recently approved for use in some situations by the US Food and Drug Administration (FDA) – target a separate disease mechanism in Alzheimer’s, the accumulation of amyloid plaques.

The phase 1 trial looked at the safety of MAPTRx, what it does to the body, and how well it targets the gene. 

It involved the UCL Dementia Research Centre, was supported by The National Institute for Health and Care Research (NIHR) UCLH Biomedical Research Centre, and took place at the NIHR UCLH Clinical Research Facility at Queen Square in London.

Forty-six patients with an average age of 66 were enrolled in the trial which took place between 2017 and 2020. The trial looked at three doses of the drug, given by injection into the nervous system via the spinal canal, compared with placebo.

According to the study, the drug was well tolerated, with all patients completing the treatment period and over 90% completing the post-treatment stage.

Patients in both the treatment and placebo groups experienced either mild or moderate side effects. 

The most common was headache after injection of the drug. But no serious adverse events were seen in patients given the drug.

The research team also looked at levels of two forms of the tau protein in the central nervous system (CNS) – a reliable indicator of disease – over the duration of the study.

They found a greater than 50% reduction in levels of total tau and phosphor tau concentration in the CNS after 24 weeks in the two treatment groups which received the highest dose of the drug.

Dr Liz Coulthard, Associate Professor in Dementia Neurology at the University of Bristol, said the study was excitingbecause it shows that we can alter the amount of tau – one of the proteins that causes Alzheimer’s disease.

“This reduction is achieved by blocking the messages from DNA that make the abnormal protein within each cell. It is a very high tech method of treating patients with Alzheimer’s. 

“We know it might be useful because a similar drug is now used successfully to treat a rare neurological condition of childhood (spinal muscular atrophy).

“As this is a phase 1 study, all it tells us is that the drug is good enough to take to full trials, i.e. the drug blocks the production of harmful protein without causing obvious dangerous side effects.

“Bigger trials are needed to test whether this effect actually helps individual patients. These trials are underway.

“This treatment works on a different protein to lecanemab, the drug recently licensed in the US and under regulatory review here.”

But she added: “One major drawback to this treatment is that it needs to be given by injection into the lumbar spine.”

Prof Tara Spires-Jones, Professor of Neurodegeneration and deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, and BNA President, said while there is a long way to go in larger trials to decide whether the drug will help people living with dementia, she described the data as “very promising.”

“This type of treatment targeting tau has the potential to slow or even hopefully stop Alzheimer’s disease progression, so I very much look forward to seeing results from the next stages of testing.”

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Tai chi outperforms conventional exercise for seniors

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New findings from 12 studies involving 2,901 participants have demonstrated that tai chi outperforms conventional exercise in improving mobility and balance in seniors.

While tai chi is understood to be beneficial for functional mobility and balance in older adults, such benefits are not well understood due to large variance in research study protocols and observations.

This new review and analysis has now shown that tai chi can induce greater improvement in functional mobility and balance in relatively healthy older adults compared to conventional exercise.

The findings showed the following performance results:

  • The time to complete 50-foot walking was 1.84 seconds faster. 
  • The time to maintain a one-leg stance was 6 seconds longer when eyes were open and 1.65 seconds longer when eyes were closed. 
  • Individuals improved their timed-up-and-go test performance by 0.18 points, indicating quicker standing, walking, and sitting.
  • Individuals taking the functional reach test showed significant improvement with a standardised mean difference of 0.7, suggesting a noteworthy positive impact on the ability to reach and perform daily activities.

Secondary analyses revealed that the use of tai chi with relatively short duration of less than 20 weeks, low total time of less than 24 total hours, and/or focusing on the Yang-style of this ancient form of Chinese martial arts were particularly beneficial for functional mobility and balance as compared to conventional exercise.

“This systematic literature review and meta-analysis are exciting because they provide strong evidence that tai chi is a more efficient strategy to improve functional mobility and balance in relatively healthy older adults, as compared to conventional exercise,” said Brad Manor, Ph.D., director of the Mobility and Falls Program at Hebrew SeniorLife’s Hinda and Arthur Marcus Institute for Aging Research, and associate professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center.

“This research suggests that tai chi should be carefully considered in future studies and routines of rehabilitative programs for balance and mobility in older adults,” said Bao Dapeng, professor at Beijing Sport University.

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New standards for biomarkers of ageing

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A paper has put forward a new framework for standardising the development and validation of biomarkers of ageing to better predict longevity and quality of life.

Led by Harvard researchers, the team has zeroed in on biomarkers of ageing using omic data from population-based studies. 

The team included ageing and longevity expert Alex Zhavoronkov, PhD, founder and CEO of AI-driven drug discovery company Insilico Medicine, and the findings appeared in Nature Medicine

Ageing is associated with a number of biological changes including increased molecular and cellular damage, however, researchers do not yet have a standardised means to evaluate and validate biomarkers related to ageing. 

In order to create those standards as well as actionable clinical tools, the team analysed population-based cohort studies built on omic data (data related to biological molecules which can include proteomics, transcriptomics, genomics, and epigenomics) of blood-based biomarkers of ageing. The researchers then compared the predictive strength of different biomarkers, including study design and data collection approaches, and looked at how these biomarkers presented in different populations. 

In order to better assess the impact of ageing using biomarkers, the researchers found that clinicians needed to expand their focus to consider not only mortality as an outcome, but also how biomarkers of aging are associated with numerous other health outcomes, including functional decline, frailty, chronic disease, and disability. They also call for the standardisation of omic data to improve reliability. 

“Omics and biomarkers harmonisation efforts, such as the Biolearn project, are instrumental in validation of biomarkers of aging” said co-first author Mahdi Moqri, PhD, of the Division of Genetics. 

Biolearn is an open-source project for biomarkers of aging and is helping to harmonise existing ageing biomarkers, unify public datasets, and provide computational methodologies.

The team also emphasised the importance of continued collaborations among research groups on “large-scale, longitudinal studies that can track long-term physiological changes and responses to therapeutics in diverse populations”, and that further work is required to understand how implementation of biomarker evaluation in clinical trials might improve patient quality of life and survival.

“If we hope to have clinical trials for interventions that extend healthy lifespan in humans, we need reliable, validated biomarkers of ageing,” said co-first author Jesse Poganik, PhD, of the Division of Genetics. 

“We hope that our framework will help prioritise the most promising biomarkers and provide health care providers with clinically valuable and actionable tools.”

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Healthy aging research to receive $115 million

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Global non-profit Hevolution Foundation has announced $115 million in funding that makes up 49 new awards under its Geroscience Research Opportunities (HF-GRO) programme.  

As part of Hevolution’s mission to catalyse the healthspan scientific ecosystem and drive transformative breakthroughs in healthy aging, HF-GRO is funding promising pre-clinical research in aging biology and geroscience. 

Through this first wave of HF-GRO awards, Hevolution will invest up to $115 million in this first cohort of 49 selected projects over the next five years. Its second call for proposals under HF-GRO will be announced later this year, offering an additional $115 million to address the significant funding gaps in aging research.  

Dr. Felipe Sierra, Hevolution’s Chief Scientific Officer stated: “These 49 important research projects represent a significant step forward in deepening our understanding of healthy aging. Hevolution’s prime objective is to mobilise greater investment around uncovering the foundational mechanisms behind biological aging. 

“We are steadfast in our belief that by examining the root causes of aging, rather than solely focusing on its associated diseases, we can usher in a brighter future for humanity.” 

HF-GRO awardees include researchers at prestigious institutions across the United States, Canada, and Europe, including the U.S. National Institute on Aging, Brigham and Women’s Hospital, the Buck Institute, the Mayo Clinic, New York University, and the University of California San Francisco, among many others. 

The American Federation for Aging Research is providing programmatic support for the HF-GRO program, with grantees selected through a rigorous two-stage peer-review process involving 100 experts in aging biology and geroscience. 

Dr Berenice Benayoun, an HF-GRO grant recipient at the University of Southern California, stated: “I am extremely honored and excited that Hevolution selected our project for funding. This is a project close to my heart, which aims at understanding why and how the female and male innate immune aging differs. 

“This funding will support us as we start laying the foundation for a lasting improvement of women’s health throughout aging.” 

To date, Hevolution has committed approximately $250 million to transform the healthy aging sector, including the $40 million for specialised research and development in healthspan science recently announced at Hevolution’s Global Healthspan Summit. 

Hevolution is ramping up its investments to enable healthier aging for all and is now the second largest funder of aging biology research worldwide.  

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