MC3R

EMERYVILLE, Calif.--( BUSINESS WIRE )-- Nutcracker Therapeutics, Inc. , a biotechnology company dedicated to developing transformative RNA therapies through its proprietary technology platform, today announced the publication of its latest peer-reviewed paper, which explores the fundamental aspects of its Nutshell ® platform of peptoid-based mRNA delivery vehicles. The paper, published in ACS Nano , outlines the design of these peptoids, their impact on mRNA expression, and comparisons to lipid nanoparticle (LNP) delivery vehicles. mRNA vaccines and therapeutics are typically delivered using LNP formulations, which have known liver-bias and immunogenicity issues. Instead of using traditional lipids, Nutcracker Therapeutics chose peptoids as the macromolecule core of its technology. Peptoids are similar in structure to the peptides found ubiquitously in nature with a key difference: The side chain groups are attached to the amide nitrogen instead of the alpha carbon – a minor change with drastic implications for nanoparticle properties. Chief among these is the high level of tuning and customization that can be achieved by modifying the side chains of the peptoids, which can confer properties such as organ-targeting, increasing expression, and more. This study sought to systematically characterize Nutcracker Therapeutics’ peptoid-based delivery vehicles and compare their performance to benchmark traditional LNPs. The scientists synthesized and characterized 221 different peptoid molecules, and clustered that library based on physico-chemical properties. The most promising cluster was then selected as a structural motif for further optimization. Ultimately, a high-expressing liver-targeted peptoid was identified which performed better than the benchmark lipid MC3 in inducing expression levels of an mRNA-encoded, anti-RSV protein in mice. Additionally, this peptoid showed limited reactogenicity in mice and was storage stable for longer than six months. “As the mRNA therapeutics field expands, there is an increased need to understand and control delivery vehicle properties,” remarked Bette Webster, Senior Scientist and lead author on the study. “We demonstrate that peptoids are a flexible and modular replacement for ionizable lipids that facilitate tunable nanoparticles for a range of therapeutic areas. We build relationships between peptoid structure and in vivo expression that can be applied not only to the problem of IV delivery but also more focused applications.” Additional findings from this paper include: Peptoid macromolecules can be further fine tuned to direct the localization of Nutshell ® delivery vehicles among the major target organs: lung, spleen, and liver Delivery of anti-RSV-encoding mRNA with peptoid-based Nutshell ® particles led to a roughly two-fold higher expression of the resulting protein 24 hours post-administration compared to MC3 at the same dose level Peptoids showed limited in vivo reactogenicity, based on serum levels of proinflammatory cytokines six hours post-administration in Balb/c mice. These markers of immunogenic response included interleukin-2, interleukin-6, TNF alpha, and interferon gamma Nutshell ® delivery vehicles were stable for six months in -80°C storage, with no growth in delivery vehicle diameter, changes in encapsulation, or impact to RNA integrity. The stored delivery vehicles did not show changes in protein expression, while also having several-fold higher expression versus stored MC3 “At Nutcracker Therapeutics, we believe that mRNA will be the modality of choice to treat a wide range of diseases – from the common to the exceedingly difficult. Unlocking this reality will require RNA-specific tools and processes,” commented Chief Scientific Officer Samuel Deutsch, Ph.D. “Our Nutshell ® delivery vehicles exemplify this philosophy, as we found ways to improve the current mRNA delivery paradigm, instead of relying on the same delivery tools employed throughout the industry. Each part of our platform – from the drug design process with the CodonCracker™ software, to the biochip-based Nutcracker ® Manufacturing Unit and Nutshell ® delivery vehicles – was built to simplify mRNA drug development, allowing us to create therapies with complex mechanisms and unique properties.” The paper titled, “Discovery of a peptoid-based nanoparticle platform for therapeutic mRNA delivery via diverse library clustering and structural parameterization,” can be found online on the ACS Nano website . About Nutcracker Therapeutics, Inc. Nutcracker Therapeutics, Inc. is an RNA therapeutics company that has combined the power of advanced engineering with high-precision biosynthesis to deploy a complete RNA platform that encompasses the design, delivery, and manufacturing of RNA medicines. Armed with this high-tech advantage, the company has initiated multiple therapeutic programs with the support of clinical investigators at leading institutions. Nutcracker Therapeutics’ technology platform has the potential to significantly reduce costs and cycle times for RNA therapeutic development, with dramatic advantages in speed and capacity scaling over other RNA manufacturing approaches. For more information, visit www.nutcrackerx.com .

Genes can indirectly influence the age at which girls have their first period by accelerating weight gain in childhood, a known risk factor for early puberty. Other genes can directly affect age of puberty, some with profound effects. Genes can indirectly influence the age at which girls have their first period by accelerating weight gain in childhood, a known risk factor for early puberty, a Cambridge-led study has found. Other genes can directly affect age of puberty, some with profound effects. In the largest study of its kind to date, an international team led by researchers at the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, studied the DNA of around 800,000 women from Europe, North America, China, Japan, and Korea. Published today in Nature Genetics, the researchers found more than 1,000 variants -- small changes in DNA -- that influence the age of first menstrual period. Around 600 of these variants were observed for the first time. The age at which girls hit puberty and start having periods normally occurs between ages 10 to 15, though this has been getting earlier and earlier in recent decades. The reasons for this are not fully understood. Early puberty is linked with increased risk of a number of diseases in later life, including type 2 diabetes, cardiovascular disease, and certain cancers. Later puberty on the other hand, has been linked to improved health in adulthood and a longer lifespan. Just under half (45%) of the discovered genetic variants affected puberty indirectly, by increasing weight gain in early childhood. Corresponding author Professor John Perry said: "Many of the genes we've found influence early puberty by first accelerating weight gain in infants and young children. This can then lead to potentially serious health problems in later life, as having earlier puberty leads to higher rates of overweight and obesity in adulthood." Previous work by the team -- together with researchers at Cambridge's MRC Metabolic Diseases Unit -- showed that a receptor in the brain, known as MC3R, detects the nutritional state of the body and regulates the timing of puberty and rate of growth in children, providing a mechanism by which this occurs. Other identified genes appeared to be acting in the brain to control the release of reproductive hormones. The scientists also analysed rare genetic variants that are carried by very few people, but which can have large effects on puberty. For example, they found that one in 3,800 women carry variants in the gene ZNF483, which caused these women to experience puberty on average, 1.3 years later. Dr Katherine Kentistou, lead study investigator, added: "This is the first time we've ever been able to analyse rare genetic variants at this scale. We have identified six genes which all profoundly affect the timing of puberty. While these genes were discovered in girls, they often have the same impact on the timing of puberty in boys. The new mechanisms we describe could form the basis of interventions for individuals at risk of early puberty and obesity." The researchers also generated a genetic score that predicted whether a girl was likely to hit puberty very early or very late. Girls with the highest 1% of this genetic score were 11 times more likely to have extremely delayed puberty -- that is, after age 15 years. On the other hand, girls with the lowest 1% genetic score were 14 times more likely to have extremely early puberty -- before age 10. Senior author and paediatrician Professor Ken Ong said: "In the future, we may be able to use these genetic scores in the clinic to identify those girls whose puberty will come very early or very late. The NHS is already trialling whole genome sequencing at birth, and this would give us the genetic information we need to make this possible. "Children who present in the NHS with very early puberty -- at age seven or eight -- are offered puberty blockers to delay it. But age of puberty is a continuum, and if they miss this threshold, there's currently nothing we have to offer. We need other interventions, whether that's oral medication or a behavioural approach, to help. This could be important for their health when they grow up." The research was supported by the Medical Research Council and included data from the UK Biobank.