Insomnia, Fatal Familial

Scientists have developed a gene-silencing tool that shows promise as a therapy against fatal prion diseases. The tool, a streamlined epigenetic editor, paves the way for a new class of genetic approaches to treat certain diseases. Drug development is typically slow: the pipeline from basic research discoveries that provide the basis for a new drug to clinical trials to production of a widely available medicine can take decades. But decades can feel impossibly far off to someone who currently has a fatal disease. Broad Institute Senior Group Leader Sonia Vallabh is acutely aware of that race against time, because the topic of her research is a neurodegenerative and ultimately fatal disease-fatal familial insomnia, a type of prion disease-that she will almost certainly develop as she ages. Vallabh and her husband, Eric Minikel, switched careers and became researchers after they learned that Vallabh carries a disease-causing version of the prion protein gene and that there is no effective therapy for fatal prion diseases. The two now run a lab at Broad Institute where they are working to develop drugs that can prevent and treat these diseases, and their deadline for success is not based on grant cycles or academic expectations but on the ticking time bomb in Vallabh's genetic code. That is why Vallabh was excited to discover, when she entered into a collaboration with Whitehead Institute Member Jonathan Weissman, that Weissman's group likes to work at full throttle. In less than two years, Weissman, Vallabh, and their collaborators have developed a set of molecular tools called CHARMs that can turn off disease-causing genes such as the prion protein gene -- as well as, potentially, genes coding for many other proteins implicated in neurodegenerative and other diseases -- and they are refining those tools to be good candidates for use in human patients. Although the tools still have many hurdles to pass before the researchers will know if they work as therapeutics, the team is encouraged by the speed with which they have developed the technology thus far. "The spirit of the collaboration since the beginning has been that there was no waiting on formality," Vallabh says. "As soon as we realized our mutual excitement to do this, everything was off to the races." Co-corresponding authors Weissman and Vallabh and co-first authors Edwin Neumann, a graduate student in Weissman's lab, and Tessa Bertozzi, a postdoc in Weissman's lab, describe CHARM -- which stand for Coupled Histone tail for Autoinhibition Release of Methyltransferase -- in a paper published in the journal Science on June 27. "With the Whitehead and Broad Institutes right next door to each other, I don't think there's any better place than this for a group of motivated people to move quickly and flexibly in the pursuit of academic science and medical technology," says Weissman, who is also a professor of biology at the Massachusetts Institute of Technology and an HHMI Investigator. "CHARMs are an elegant solution to the problem of silencing disease genes, and they have the potential to have an important position in the future of genetic medicines." To treat a genetic disease, target the gene Prion disease, which leads to swift neurodegeneration and death, is caused by the presence of misshapen versions of the prion protein. These cause a cascade effect in the brain: the faulty prion proteins deform other proteins, and together these proteins not only stop functioning properly but also form toxic aggregates that kill neurons. The most famous type of prion disease, known colloquially as mad cow disease, is infectious, but other forms of prion disease can occur spontaneously or be caused by faulty prion protein genes. Most conventional drugs work by targeting a protein. CHARMs, however, work further upstream, turning off the gene that codes for the faulty protein so that the protein never gets made in the first place. CHARMs do this by epigenetic editing, in which a chemical tag gets added to DNA in order to turn off or silence a target gene. Unlike gene editing, epigenetic editing does not modify the underlying DNA -- the gene itself remains intact. However, like gene editing, epigenetic editing is stable, meaning that a gene switched off by CHARM should remain off. This would mean patients would only have to take CHARM once, as opposed to protein-targeting medications that must be taken regularly as the cells' protein levels replenish. Research in animals suggests that the prion protein isn't necessary in a healthy adult, and that in cases of disease, removing the protein improves or even eliminates disease symptoms. In a person who hasn't yet developed symptoms, removing the protein should prevent disease altogether. In other words, epigenetic editing could be an effective approach for treating genetic diseases such as inherited prion diseases. The challenge is creating a new type of therapy. Fortunately, the team had a good template for CHARM: a research tool called CRISPRoff that Weissman's group previously developed for silencing genes. CRISPRoff uses building blocks from CRISPR gene editing technology, including the guide protein Cas9 that directs the tool to the target gene. CRISPRoff silences the targeted gene by adding methyl groups, chemical tags that prevent the gene from being transcribed or read into RNA and so from being expressed as protein. When the researchers tested CRISPRoff's ability to silence the prion protein gene, they found that it was effective and stable. Several of its properties, though, prevented CRISPRoff from being a good candidate for a therapy. The researchers' goal was to create a tool based on CRISPRoff that was just as potent but also safe for use in humans, small enough to deliver to the brain, and designed to minimize the risk of silencing the wrong genes or causing side effects. From research tool to drug candidate Led by Neumann and Bertozzi, the researchers began engineering and applying their new epigenome editor. The first problem that they had to tackle was size, because the editor needs to be small enough to be packaged and delivered to specific cells in the body. Delivering genes into the human brain is challenging; many clinical trials have used adeno-associated viruses (AAVs) as gene-delivery vehicles, but these are small and can only contain a small amount of genetic code. CRISPRoff is way too big; the code for Cas9 alone takes up most of the available space. The Weissman lab researchers decided to replace Cas9 with a much smaller zinc finger protein (ZFP). Like Cas9, ZFPs can serve as guide proteins to direct the tool to a target site in DNA. ZFPs are also common in human cells, meaning they are less likely to trigger an immune response against themselves than the bacterial Cas9. Next, the researchers had to design the part of the tool that would silence the prion protein gene. At first, they used part of a methyltransferase, a molecule that adds methyl groups to DNA, called DNMT3A. However, in the particular configuration needed for the tool, the molecule was toxic to the cell. The researchers focused on a different solution: instead of delivering outside DNMT3A as part of the therapy, the tool is able to recruit the cell's own DNMT3A to the prion protein gene. This freed up precious space inside of the AAV vector and prevented toxicity. The researchers also needed to activate DNMT3A. In the cell, DNMT3A is usually inactive until it interacts with certain partner molecules. This default inactivity prevents accidental methylation of genes that need to remain turned on. Neumann came up with an ingenious way around this by combining sections of DNMT3A's partner molecules and connecting these to ZFPs that bring them to the prion protein gene. When the cell's DNMT3A comes across this combination of parts, it activates, silencing the gene. "From the perspectives of both toxicity and size, it made sense to recruit the machinery that the cell already has; it was a much simpler, more elegant solution," Neumann says. "Cells are already using methyltransferases all of the time, and we're essentially just tricking them into turning off a gene that they would normally leave turned on." Testing in mice showed that ZFP-guided CHARMs could eliminate more than 80% of the prion protein in the brain, while previous research has shown that as little as 21% elimination can improve symptoms. Once the researchers knew that they had a potent gene silencer, they turned to the problem of off-target effects. The genetic code for a CHARM that gets delivered to a cell will keep producing copies of the CHARM indefinitely. However, after the prion protein gene is switched off, there is no benefit to this, only more time for side effects to develop, so they tweaked the tool so that after it turns off the prion protein gene, it then turns itself off. Meanwhile, a complementary project from Broad Institute scientist and collaborator Benjamin Deverman's lab, focused on brain-wide gene delivery and published in Science on May 17, has brought the CHARM technology one step closer to being ready for clinical trials. Although naturally occurring types of AAV have been used for gene therapy in humans before, they do not enter the adult brain efficiently, making it impossible to treat a whole-brain disease like prion disease. Tackling the delivery problem, Deverman's group has designed an AAV vector that can get into the brain more efficiently by leveraging a pathway that naturally shuttles iron into the brain. Engineered vectors like this one make a therapy like CHARM one step closer to reality. Thanks to these creative solutions, the researchers now have a highly effective epigenetic editor that is small enough to deliver to the brain, and that appears in cell culture and animal testing to have low toxicity and limited off-target effects. "It's been a privilege to be part of this; it's pretty rare to go from basic research to therapeutic application in such a short amount of time," Bertozzi says. "I think the key was forming a collaboration that took advantage of the Weissman lab's tool building experience, the Vallabh and Minikel lab's deep knowledge of the disease, and the Deverman lab's expertise in gene delivery." Looking ahead With the major elements of the CHARM technology solved, the team is now fine-tuning their tool to make it more effective, safer, and easier to produce at scale as will be necessary for clinical trials. They have already made the tool modular, so that its various pieces can be swapped out and future CHARMs won't have to be programmed from scratch. CHARMs are also currently being tested as therapeutics in mice. The path from basic research to clinical trials is a long and winding one, and the researchers know that CHARMs still have a way to go before they might become a viable medical option for people with prion diseases, including Vallabh, or other diseases with similar genetic components. However, with a strong therapy design and promising laboratory results in hand, the researchers have good reason to be hopeful. They continue to work at full throttle, intent on developing their technology so that it can save patients' lives not someday, but as soon as possible.

BERWYN, Pa., Sept. 13, 2022 /PRNewswire/ -- (NYSE: ANVS) Annovis Bio ("Annovis" or the "Company"), a clinical-stage drug platform company addressing neurodegenerative diseases, announced today the publication of three granted US patents – US11400075 (link), US11376238 (link), and US11382893 (link). The patents cover methods of treating amyloid lateral sclerosis (ALS), Huntington's disease, and prion diseases by administering buntanetap. They will provide intellectual property protection through 2031, prior to any patent extensions. The patents strengthen and expand the Company's intellectual property portfolio. The Company now has issued patents covering a wide range of neurodegenerative diseases, including Alzheimer's disease (AD), alpha-synucleopathies, such as Parkinson's disease (PD), tauopathies, such as frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE) and acute injuries such as stroke and traumatic brain injury. "These additional patents represent further proof for our platform drug, buntanetap, which acts on a variety of neurodegenerative disorders by inhibiting multiple neurotoxic proteins," said Maria L. Maccecchini, Ph.D., Founder, President, and CEO of Annovis. Summary of key coverage: A method of treating amyloid lateral sclerosis, a rare progressive neurodegenerative disorder, by administering buntanetap and inhibiting the synthesis of superoxide dismutase protein1 and TDP43. A method of treating Huntington's disease, a rare progressive neurodegenerative disorder, by administering buntanetap and inhibiting the synthesis of Huntingtin protein. A method of treating prion diseases, a family of ultra-rare progressive neurodegenerative disorders, by administering buntanetap. There is additional coverage of particular Prion diseases, including scrapie prion, transmissible mink encephalopathy (TME), chronic wasting disease (CWD), bovine spongiform encephalopathy (BSE) prion, feline spongiform encephalopathy (FSE), exotic ungulate encephalopathy (EUE), kuru prion, Creutzfeldt-Jakob disease (CJD), Variant Creutzfeldt-Jakob disease (vCJD, nvCJD), Gerst-mann-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI) prion. About Buntanetap Buntanetap (previously known as ANVS401 or Posiphen) is an oral translational inhibitor of neurotoxic aggregating proteins (TINAPs), which mode of action leads to a lower level of neurotoxic proteins and consequently less toxicity in the brain. In a Phase 2a clinical trial in AD and PD patients, buntanetap was shown to be well-tolerated and safe, and its pharmacokinetics were found to be in line with levels measured earlier in humans, meeting both the primary and secondary endpoints. Additionally, exploratory endpoints were also met, as treatment with buntanetap resulted in statistically significant improvement in motor function in PD patients and cognition in AD patients. Presently buntanetap is being studied in a phase 3 early PD study and will enter a phase 2/3 study in AD patients later in the year. About Annovis Bio, Inc. Headquartered in Berwyn, Pennsylvania, Annovis Bio, Inc. is a clinical-stage, drug platform company developing transformative therapies that treat neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and other chronic and acute neurodegenerative diseases. The Company believes that it is the only company developing a drug that inhibits more than one neurotoxic protein, improves the information highway of the nerve cell, known as axonal transport, reduces inflammation and protects nerve cells from dying in chronic and acute neurodegeneration. Annovis conducted two Phase 2 studies: one in AD patients and one in both AD and PD patients. In the AD/PD study, buntanetap showed improvements in cognition and memory in AD as well as body and brain function in PD patients. For more information on Annovis Bio, please visit the Company's website and follow us on LinkedIn and Twitter. Forward-Looking Statements Statements in this press release contain "forward-looking statements" that are subject to substantial risks and uncertainties. Forward-looking statements contained in this press release may be identified by the use of words such as "anticipate," "expect," "believe," "will," "may," "should," "estimate," "project," "outlook," "forecast" or other similar words, and include, without limitation, statements regarding the timing, effectiveness, and anticipated results of buntanetap clinical trials. Forward-looking statements are based on Annovis Bio, Inc.'s current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. These and other risks and uncertainties are described more fully in the section titled "Risk Factors" in the Annual Report on Form 10-K for the year ended December 31, 2021, filed with the Securities and Exchange Commission. Forward-looking statements contained in this announcement are made as of this date, and Annovis Bio, Inc. undertakes no duty to update such information except as required under applicable law. Media and Investor Contact: Nic Johnson Russo Partners, LLC (303) 482-6405 nic.johnson@russopartnersllc.com Company Codes: NYSE:ANVS

Maximum Demand for Human Prion Disease Diagnostics to Concentrate in North America with the U.S. at the Forefront Fact.MR’s survey on the human prion disease diagnostic market offers insights into key trends and opportunities affecting growth in the market. It studies scope for expansion across various segments in terms of technology. The report presents analysis of growth drivers, challenges, and recent developments influencing sales of human prion disease diagnostics worldwide. Fact.MR – A Market Research and Competitive Intelligence Provider: Fact.MR’s latest study analyses the growth trajectory of the human prion disease diagnostic market. Human prion diseases (transmissible spongiform encephalopathies, TSEs) are rare, progressive, and fatal neurogenerative diseases caused by the aggregation of misfolded prion protein in neuronal tissue. Because they pose a high risk of transmission, these diseases are under active surveillance in several countries. Thanks to ongoing technological advancements in the healthcare sector, medical professionals are able to develop solutions that facilitate the early diagnosis of such diseases. Considering this, Fact.MR has projected the global human prion diseases diagnostics market to expand at a steady pace over the forecast period 2021-2031. As per the article titled “Infectious Diseases of Poverty” published by the National Centre for Biotechnology Information (NCBI), types of these diseases include Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. The article states that currently there are no specific therapeutic and prophylactic interventions available for the treatment of human prion diseases. Steady progress in the field of clinical diagnostics and soaring concerns pertaining to causes, symptoms, and types of human prior diseases will create conducive environment for the expansion of the market. Request a report sample to gain comprehensive insights at Several government organizations are providing research and development aids to facilitate the development of treatment options and diagnosis for prion diseases. This is anticipated to offer lucrative opportunities for market players in the forthcoming years. As per Fact.MR, China is expected to emerge as an attractive pocket in the global human prion disease diagnostics market. Increasing adoption of technologically advanced and digital solutions in the healthcare sector is expected to fuel sales of human prion disease diagnostic solutions in China. “Government-backed investment in research of diagnostic methods and drug development in various countries is anticipated to drive the human prion diseases diagnostics market. Besides this, awareness programs launched by non-profit organizations in emerging economies will continue fueling the demand for human prion disease diagnostics over the assessment period," says the Fact.MR analyst. Key Takeaways from Human Prion Disease Diagnostics Market Survey Demand for human prion disease diagnostics is projected to rise in the U.S. owing to the presence of robust healthcare infrastructure. Rising awareness regarding health and wellness and initiatives launched by non-profit to educate common men about types and symptoms of the disease will drive sales in India and China. The U.K. is projected to continue exhibiting high demand for human prion disease diagnostics. Growth in the market will be steered by digitization of medical procedures and diagnostics. Expansion of healthcare sector will support growth in Japan. Growth Drivers: Advancements in magnetic resonance imaging (MRI) procedures and equipment are anticipated to fuel sales of human prion disease diagnostic solutions. Expansion of the life science sector in emerging economies will continue propelling demand for human prion disease diagnostics. To gain in-depth insights on Human Prion Disease Diagnostics Market, request methodology at Competitive Landscape Companies operating in the global human prion disease diagnostic market are actively investing in research and development to develop accurate and easily accessible prion disease diagnostic solutions. Besides this, mergers, acquisitions, and collaborations are expected to assist market players in solidifying growth prospects over the forecast period. For instance, Bio-rad Laboratories has launched its Western Blot Sample Testing for the diagnosis of various human prion diseases. Similarly, Novartis AG and its team of researchers have started combining expertise and cutting-edge technology to develop effective prion disease diagnostic solutions. The products will be ready to be launched in the market soon. Key Players in the Human Prion Disease Diagnostic Market Include: PrioSense Ltd. Bio-Rad Laboratories, Inc. Abbott Diagnostics, Inc. Gradipore Inc. Prionics AG Prion Development Laboratories Beckman Coulter Novartis AG Covance, Inc. Gene Thera, Inc. More Valuable Insights on Human Prion Disease Diagnostic Market Fact.MR provides an unbiased analysis of the human prion disease diagnostic market, presenting historical demand data (2016-2020) and forecast statistics for the period from 2021-2031. The study divulges compelling insights on the global human prion disease diagnostic market with a detailed segmentation on the basis of: Technology: Electroencephalography Magnetic Resonance Imaging Cerebrospinal Fluid Examination Computed Tomography Tonsil Biopsy Brain Biopsy Blood Tests Neurological Examinations Regions: North America Latin America Europe East Asia South Asia Oceania MEA Key Questions Covered in the Human Prion Disease Diagnostic Market Report The report offers insight into human prion disease diagnostic market demand outlook for 2021-2031 The market study also highlights projected sales growth for human prion disease diagnostic market between 2021 and 2031 Human prion disease diagnostic market survey identifies key growth drivers, restraints, and other forces impacting prevailing trends and evaluation of current market size and forecast and technological advancements within the industry Human prion disease diagnostic market share analysis of the key companies within the industry and coverage of strategies such as mergers & acquisitions, joint ventures, collaborations or partnerships, and others Explore Fact.MR’s Coverage on the Healthcare Domain – Rare Neurodegenerative Disease Treatment Market- Market participants are increasing their investments in medication development for the treatment of neurodegenerative diseases, and patients are becoming more aware of the various therapeutic choices available. In the long run, the rise in medical tourism and investments in modernizing healthcare infrastructure across Asia Pacific's developing countries are projected to benefit the rare neurodegenerative disease treatment market. Long-term growth will be aided by advances in medical technology for the diagnosis and treatment of various ailments. Rare Neurological Disease Treatment Market- The incidence of rare diseases, the evolving trend of orphan drugs, and rising healthcare spending have all contributed to a significant increase in overall sales of rare neurological treatments during the previous decade. Furthermore, the rare neurological disease treatment market is expected to be the most attractive market among the rare disease treatment markets. Rapid advancements in healthcare, as well as major socioeconomic shifts that result in altered lifestyles, are allowing manufacturers to increase their footprint in the rare neurological disease treatment market. Intraoperative MRI Equipment Market- Intraoperative MRI equipment is becoming more popular around the world. Manufacturers of medical devices are working to improve the efficiency of intraoperative MRI equipment for operation localization. Physicians can now study images during a neurosurgical procedure rather than referring to prior and postoperative images thanks to this technology. New intraoperative MRI equipment on the market now allows for real-time viewing throughout all stages of brain surgery, which is expected to increase demand in the future years. About Fact.MR Market research and consulting agency with a difference! That’s why 80% of Fortune 1,000 companies trust us for making their most critical decisions. We have offices in US and Dublin, whereas our global headquarter is in Dubai. While our experienced consultants employ the latest technologies to extract hard-to-find insights, we believe our USP is the trust clients have on our expertise. Spanning a wide range – from automotive & industry 4.0 to healthcare & retail, our coverage is expansive, but we ensure even the most niche categories are analyzed. Reach out to us with your goals, and we’ll be an able research partner. Contact: Mahendra Singh US Sales Office 11140 Rockville Pike Suite 400 Rockville, MD 20852 United States Tel: +1 (628) 251-1583 E: sales@factmr.com Source: Fact.MR