It was in 1959 when an extra chromosome on the 21st pair in the human cell was discovered by French geneticist Jerome Jean Louis Marie Lejeune. This was followed by research in the discipline of cytogenetics - the study of chromosomes. This chromosomal aberration which affects around one in 1000 live births worldwide, is called trisomy 21 or Down syndrome - named after the British physician who characterized the condition.\n\n\n\nFollowing the discovery, the first mouse model with Down syndrome was created in 1974 which brought about guidelines for studying other chromosomal abnormalities. \n\n\n\nSoon enough, prenatal diagnostic measures like amniocentesis were introduced to detect a fetus with Down syndrome.\n\n\n\nOver the years, therapies have been focused on individual physical and intellectual needs, and to battle comorbidities like heart defects and hypothyroidism. Early intervention programs are offered to young children with Down syndrome where they engage with professionals who aid in providing speech and physical therapy, among other assistance. \n\n\n\nAlthough amino acid supplements have been prescribed to people with cognitive disorders as a result of the condition to influence brain activity, recent clinical trials demonstrated adverse side effects. As studies have involved only a few participants, drugs to treat symptoms of dementia in Down syndrome have not proven to be efficacious yet.\n\n\n\nHowever, news drug trials are attempting to fight symptoms, and assistive devices like special pencils to make writing easier, touch screen gadgets and large-letter keyboards have been developed to enhance learning in children.\n\n\n\nAs we observe World Down Syndrome Day on March 21, here are some of the latest advancements in Down syndrome research.\n\n\n\nNew research establishes link between senescence and Down syndrome\n\n\n\nAlthough the triplication of chromosome 21 (T21) is an established fact, very little has been known about its effect on transcription in the nucleus of cells.\n\n\n\nHowever, a study conducted by researchers at the Massachusetts Institute of Technology (MIT) in the U.S., has shed light on the interplay between T21 and transcriptome, which is the sequence of messenger RNA molecules. \n\n\n\nIt was found that, unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit chromosomal introversion - characterized by more genetic interaction within each chromosome rather than among them - and changes in chromatin accessibility - a factor that influences the regulation of gene transcription. The research findings have indicated a link between Down syndrome and senescence (associated with aging), affecting neurodevelopment.\n\n\n\nThe treatment of the T21-harboring NPCs with senolytic drugs, which selectively clear senescent cells, alleviated some of the biological dysfunctions associated with Down syndrome, according to Fady Riad, CEO of consulting firm Centurion Life Sciences. \n\n\n\nRiad expressed that “senolytics like dasatinib and quercetin might be potential therapeutic options for patients since they may alleviate cellular and molecular dysfunction in NPCs.”\n\n\n\nClinical trials for new drug to potentially improve cognitive function in people with Down syndrome begin\n\n\n\nThe Spanish Hospital del Mar Medical Research Institute is conducting a phase 1b clinical trial to test the safety and efficacy of a new treatment to improve cognitive function in people with Down syndrome.\n\n\n\nAs studies have shown that people with Down syndrome have a hyperactivated CB1 cannabinoid receptor, the drug candidate is based on the modulation of the receptor with specific inhibitors which has proven to be effective on animal models. The French biotech Aelis Farma developed AF0217, a molecule that counteracts the hyperactivity of CB1 cannabinoid in the brain.\n\n\n\nWith funding from the European Union (EU), the team at the Spanish Hospital del Mar Medical Research had previously conducted a trial phase for AF0217, which was approved by the Spanish Agency for Medicines and Health Products (AEMPS), after having demonstrated that the molecule is well-tolerated. \n\n\n\nLead researcher Rafael de la Torre commented that this was "of particular importance for the acceptance of treatment by the families of people with Down syndrome."\n\n\n\nPhase 1b trials have recruited 45 patients with Down syndrome aged between 18 and 35.\n\n\n\nAccording to Riad: “This development is part of a wave of growing interest in the therapeutic potential of modulating the endocannabinoid system.”\n\n\n\nVaccine trials to begin for the prevention of Alzheimer’s disease for people with Down syndrome \n\n\n\nPeople with Down syndrome are often at the risk of being diagnosed with Alzheimer’s disease (AD), with a 90% lifetime incidence of AD. This is because amyloid plaques - protein clumps that collect between neurons and disrupt cell function, an indicator of Alzheimer’s - are often found in individuals in their 40s with Down syndrome, because of excessive amyloid plaque formation due to the extra copy of the APP gene encoding the amyloid precursor protein found on chromosome 21.\n\n\n\nTo battle Alzheimer’s, Swiss biotech AC Immune developed a vaccine candidate that inhibits plaque formation in the brain. The ACI-24.060 vaccine is designed to elicit an antibody response by the patient’s own immune system against pathological species of amyloid beta, according to Andrea Pfeifer, CEO of AC Immune. The mechanism is similar to that of Leqembi, an FDA-approved drug for the treatment of AD.\n\n\n\nThe vaccine, which is being studied in the ongoing phase 1/2 ABATE trial in Alzheimer’s disease, will be administered to the first individual from a Down syndrome cohort soon. This follows having successfully completed an early stage clinical trial which demonstrated its safety and immunogenicity in people with Down syndrome.\n\n\n\nPfeifer said: “The lack of treatment options to address amyloid pathology in Down syndrome is unacceptable, as people living with Down syndrome represent the largest population with early onset Alzheimer’s disease. The individuals themselves together with their families are searching for therapies to help improve their quality of life and, as our first clinical study has shown, are willing to participate actively in the development of a solution.”\n\n\n\n“An effective vaccine could potentially offer a means of prevention or reduction of disease severity and have a major impact on the lives of people living with Down syndrome,” said Pfeiffer, who added that after an initial priming phase in the first year, the vaccine could be dosed annually or bi-annually as a booster to ensure that adequate antibody levels are maintained.\n\n\n\nPfeiffer expressed that the research “will further raise the profile of the unmet medical need for individuals with Down syndrome and managing Alzheimer's disease from which they almost invariably suffer.”\n\n\n\nNew drug could target Alzheimer’s disease in people with Down syndrome\n\n\n\nResearchers at the University of Arizona have developed a drug that could slow the progression of AD in people with Down syndrome. \n\n\n\nThe drug, which decreases levels of DYRK1A - an enzyme kinase which is excessively produced due to the overexpression of the DYRK1A gene in patients with AD - has exhibited its effectiveness at suppressing AD symptoms, confirming their therapeutic potential in animal models.\n\n\n\nPreviously, DYRK1A inhibitor drugs have proven efficacy in mice models with AD, while the enzyme has been studied in Drosophila (fruit fly) with genetically engineered AD phenotypes, which showed that the overexpression of the DYRK1A gene led to photoreceptor neuron degeneration, decreased locomotion, sleep and memory loss. \n\n\n\nAccording to Riad, the results are encouraging as the “study focuses on an unmet medical need and paves the way for human clinical trials,” however, there is the challenge of proving the drug’s efficacy in human clinical trials, despite its success in preclinical studies.\n\n\n\nGonadotropin-releasing hormone therapies could improve cognitive performance, according to recent Down syndrome research \n\n\n\nA new research has confirmed a correlation between the secretion of gonadotropin-releasing hormone (GnRH), which is responsible for regulating the sex hormones and is produced in the neurons in the brain, and cognitive processes in Down syndrome. Moreover, the study showed that GnRH therapies could be given to patients with Down syndrome to boost brain connectivity. \n\n\n\nThe research conducted by a team at University of Lille in France, was initially studied in mice models with Down syndrome. It was observed that the mice had deficiencies of GnRH and an imbalance in a network of microRNAs, particularly around the trisomic regions; which affects neuronal activity, olfaction, and cognition.\n\n\n\nThe mice were then treated with cell therapy and chemogenetic interventions to produce GnRH, which showed promising results where they developed cognitive abilities similar to those of healthy mice.\n\n\n\nThis research led the team to partner with researchers at University of Lausanne in Switzerland, where trials were conducted on patients with Down syndrome. Patients were given GnRH replacement therapy drug Lutrelef every 2 hours for 6 months - a therapy which is used to treat GnRH-deficient conditions like Kallmann syndrome, a condition that delays or prevents puberty. The success of the results was demonstrated by improved cognitive performance in patients.\n\n\n\n“More large-scale trials are needed but this is encouraging because GnRH replacement therapies have long been studied in humans and their safety profile is very well understood - which means that an eventual path to regulatory approval will be rather straightforward,” said Riad.