Treatment Of Down Syndrome Research Articles

Early Chronic Fluoxetine Treatment of Ts65Dn Mice Rescues Synaptic Vesicular Deficits and Prevents Aberrant Proteomic Alterations.

Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of the cerebral cortex of fluoxetine-treated trisomic mice may provide proteomic signatures that identify therapeutic targets for DS. Subcellular fractionation of synaptosomes from cerebral cortices of age- and brain-area-matched samples from fluoxetine-treated vs. water-treated trisomic and euploid male mice were subjected to HPLC-tandem mass spectrometry. Analysis of the data revealed enrichment of trisomic risk genes that participate in regulation of synaptic vesicular traffic, pre-synaptic and post-synaptic development, and mitochondrial energy pathways during early brain development. Proteomic analysis of trisomic synaptic fractions revealed significant downregulation of proteins involved in synaptic vesicular traffic, including vesicular endocytosis (CLTA, CLTB, CLTC), synaptic assembly and maturation (EXOC1, EXOC3, EXOC8), anterograde axonal transport (EXOC1), neurotransmitter transport to PSD (SACM1L), endosomal-lysosomal acidification (ROGDI, DMXL2), and synaptic signaling (NRXN1, HIP1, ITSN1, YWHAG). Additionally, trisomic proteomes revealed upregulation of several trafficking proteins, involved in vesicular exocytosis (Rab5B), synapse elimination (UBE3A), scission of endocytosis (DBN1), transport of ER in dendritic spines (MYO5A), presynaptic activity-dependent bulk endocytosis (FMR1), and NMDA receptor activity (GRIN2A). Chronic fluoxetine treatment of Ts65Dn mice rescued synaptic vesicular abnormalities and prevented abnormal proteomic changes in adult Ts65Dn mice, pointing to therapeutic targets for potential treatment of DS.

Preclinical Development of the Na-K-2Cl Co-transporter-1 (NKCC1) Inhibitor ARN23746 for the Treatment of Neurodevelopmental Disorders.

Alterations in the expression of the Cl- importer Na-K-2Cl co-transporter-1 (NKCC1) and the exporter K-Cl co-transporter 2 (KCC2) lead to impaired intracellular chloride concentration in neurons and imbalanced excitation/inhibition in the brain. These alterations have been observed in several neurological disorders (e.g., Down syndrome and autism). Recently, we have reported the discovery of the selective NKCC1 inhibitor "compound ARN23746" for the treatment of Down syndrome and autism in mouse models. Here, we report on an extensive preclinical characterization of ARN23746 toward its development as a clinical candidate. ARN23746 shows an overall excellent metabolism profile and good brain penetration. Moreover, ARN23746 is effective in rescuing cognitive impairment in Down syndrome mice upon per os administration, in line with oral treatment of neurodevelopmental disorders. Notably, ARN23746 does not present signs of toxicity or diuresis even if administered up to 50 times the effective dose. These results further support ARN23746 as a solid candidate for clinical trial-enabling studies.

Effective of Hippotherapy and Balance-Based Torso-Weighting to Improve Standing Stability and Postural Balance in Children with Down Syndrome

Down syndrome is a genetic disorder caused by an extra abnormal presence of the 21st chromosome. Some abilities related to motor function are extensive, for example, lack of postural control, gait abnormality, and lack of balance and coordination. In addition, postural changes in Down syndrome may occur due to the difficulty of perception of responses, which impairs the feeling of the limb position and limb movements. Hippotherapy (HT) is a physical treatment, and it is defined as equine-assisted treatment in which horse movement promotes physical and physiological improvements. Strategic placement of lightweight on the torso using the balance-based torso-weighting (BBTW) method has improved stability and reduced falls in people with cerebellar ataxia but has not been tested in Down syndrome. Therefore, we examined whether torso-weighting increased standing stability and or functional movement in children with DS. A total of 30 subjects with Down syndrome were taken and grouped into two groups, with group A- 15 subjects treated with hippotherapy and group B-15 subjects treated with balanced-based torso-weighting. The baseline measurement was taken using Berg's balance scale and the time up and test (TUG test). Statistical package for social science (SPSS) version 24. The paired t-test was to find the statistical difference within the groups & Independent t-test (Student t- Test) was adopted to see the statistical difference between the groups. The procedure is done by performing hippotherapy for 4 times a week for 12 weeks for group A, and balanced-based torso weighting is performed for 4 times a week for 12 weeks for group B. Children medically diagnosed with DS and with IQ less than 50 were excluded from the study. In this study, hippo therapy with conventional treadmill training gives a better improvement in a patient with down syndrome when compared with balance-based torso weighting with conventional treadmill training. Hence, hippo therapy with conventional treadmill training would be the better treatment for down syndrome.

Down syndrome identification and classification using facial features with neural network

The medical image tool named Ultrasound imaging is used for the analysis of fetus behaviour. Due to the presence of noise the quality of these images is low. Proper filtering is required to suppress this noise. Before the fatal development analysis, it is required image processing method. The processed images are then used for the analysis and it helps to take care of the health. Down syndrome is one of the crucial chromosomal disorders. It is due to the presence of a further copy of chromosome 21. The ultrasound imaging helps to point out DS in the earlier stage of pregnancy by handling the image in an efficient manner. In this work, nasal bone identification and texturing methods are used to detect the disease. Here we designed a nasal bone identification module for the image classification as normal or abnormal. Down syndrome detection utilizes a collection of facial expression images. A compact geometric descriptor is employed for extracting the facial features from the image set. There is no specific treatment for Down syndrome. Thus, early detection and screening of this disability are the best styles for Down syndrome prevention.

Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?

The triplication of chromosome 21 causes Down syndrome (DS), a genetic disorder that is characterized by intellectual disability (ID). The causes of ID start in utero, leading to impairments in neurogenesis, and continue into infancy, leading to impairments in dendritogenesis, spinogenesis, and connectivity. These defects are associated with alterations in mitochondrial and metabolic functions and precocious aging, leading to the early development of Alzheimer’s disease. Intense efforts are currently underway, taking advantage of DS mouse models to discover pharmacotherapies for the neurodevelopmental and cognitive deficits of DS. Many treatments that proved effective in mouse models may raise safety concerns over human use, especially at early life stages. Accumulating evidence shows that fatty acids, which are nutrients present in normal diets, exert numerous positive effects on the brain. Here, we review (i) the knowledge obtained from animal models regarding the effects of fatty acids on the brain, by focusing on alterations that are particularly prominent in DS, and (ii) the progress recently made in a DS mouse model, suggesting that fatty acids may indeed represent a useful treatment for DS. This scenario should prompt the scientific community to further explore the potential benefit of fatty acids for people with DS.

Assessment of Knowledge and Awareness of Down syndrome in Ha’il City Community, KSA

Background: Down syndrome is a condition in which a person has an extra chromosome. Chromosomes are small “packages” of genes in the body. They determine how a baby’s body forms and functions as it grows during pregnancy and after birth. Typically, a baby is born with 46 chromosomes. Babies with Down syndrome have an extra copy of one of these chromosomes, chromosome 21. A medical term for having an extra copy of a chromosome is ‘trisomy.’ Down syndrome is also referred to as Trisomy 21. This extra copy changes how the baby’s body and brain develop, which can cause both mental and physical challenges for the baby. The aim: the present study builded the interest to assess the knowledge and awareness of definition, causes, symptoms, diagnosis, complication, and treatment of Down Syndrome ( DS ) in Hail City and tried to improve the false thoughts about this disease. Material: A cross-sectional survey was distributed throughout in Hail City between October 2021 to April 2022. An online questionnaire was designed. It included informed consent and 10 questions about the sociodemographic data and questions regarding signs, symptoms, complications and management about DS. It was distributed via various social media apps. Methods: SPSS for Windows v22.0 IBM Inc..SPSS for windows Rel 15.0 2006 Chicago Inc. Results: The result of the present study revealed that the overall level of awareness about Down syndrome was moderate (65.7 %). More Health education for public, online seminars and more research are needed to raise the public awareness and spotlight to patients suffering from this syndrome. Keywords: Down Syndrome, genetic disease, awareness, Ha’il, KSA,

Hyper-Rigid Phasic Organization of Hippocampal Activity But Normal Spatial Properties of CA1 Place Cells in the Ts65Dn Mouse Model of Down Syndrome

Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus usingin vivoelectrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells.SIGNIFICANCE STATEMENTRecent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.

Down syndrome detection using modified adaboost algorithm

In human body genetic codes are stored in the genes. All of our inherited traits are associated with these genes and are grouped as structures generally called chromosomes. In typical cases, each cell consists of 23 pairs of chromosomes, out of which each parent contributes half. But if a person has a partial or full copy of chromosome 21, the situation is called Down syndrome. It results in intellectual disability, reading impairment, developmental delay, and other medical abnormalities. There is no specific treatment for Down syndrome. Thus, early detection and screening of this disability are the best styles for down syndrome prevention. In this work, recognition of Down syndrome utilizes a set of facial expression images. Solid geometric descriptor is employed for extracting the facial features from the image set. An AdaBoost method is practiced to gather the required data sets and for the categorization. The extracted information is then assigned and used to instruct the Neural Network using Backpropagation algorithm. This work recorded that the presented model meets the requirement with 98.67% accuracy.

The Effectiveness of Physical Therapy in Improving Muscle Strength in Children with Down Syndrome

Increasing muscle strength in the treatment of Down syndrome represents an important stage of the intervention plan, because one of the symptoms of this disorder is a generalized hypotonia. The study was conducted on 13 patients diagnosed with Down syndrome, the physical therapy strategy envisaging the improvement of muscle strength, both analytically, on muscle groups, and globally, by using therapeutic physical exercises. At the end of the physical therapy, all of the manually tested muscles (the biceps brachii, the triceps brachii, the latissimus dorsi, the rhomboids, the quadratus lumborum, the pectoralis major, the gluteus maximus, the iliopsoas, the pelvitrochanteric muscles, the adductor muscles, the tensor fascia lata, the quadriceps, the hamstrings, the sartorius, the triceps surae, the tibialis anterior, and the peroneus muscles) changed their scores, from some initial values between 3.08 and 3.77 points, to final values between 4-02 and 4.50 points, which showed a good muscle tonicity, the children succeeding in performing their usual activities with better precision and coordination.

DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome.

Down syndrome (DS), caused by trisomy of chromosome 21, occurs in 1 of every 800 live births. Early defects in cortical development likely account for the cognitive impairments in DS, although the underlying molecular mechanism remains elusive. Here, we performed histological assays and unbiased single-cell RNA-Seq (scRNA-Seq) analysis on cerebral organoids derived from 4 euploid cell lines and from induced pluripotent stem cells (iPSCs) from 3 individuals with trisomy 21 to explore cell-type-specific abnormalities associated with DS during early brain development. We found that neurogenesis was significantly affected, given the diminished proliferation and decreased expression of layer II and IV markers in cortical neurons in the subcortical regions; this may have been responsible for the reduced size of the organoids. Furthermore, suppression of the DSCAM/PAK1 pathway, which showed enhanced activity in DS, using CRISPR/Cas9, CRISPR interference (CRISPRi), or small-molecule inhibitor treatment reversed abnormal neurogenesis, thereby increasing the size of organoids derived from DS iPSCs. Our study demonstrates that 3D cortical organoids developed in vitro are a valuable model of DS and provide a direct link between dysregulation of the DSCAM/PAK1 pathway and developmental brain defects in DS.

Down Syndrome and Cell Therapy: A Review

Cell therapy has been considered as an alternative treatment for many diseases, including Down syndrome (DS). However, this treatment remained debatable due to insufficient clinical data. Therefore, this study aims to identify and evaluate studies on the potential of cell therapy in improving the quality of life of DS patients. Relevant English articles and snowball sampling from Science Direct and PubMed (published until August 2019) on the effects of cell therapy on DS was retrieved. Only original articles on the effect of cell therapy in DS patients or Ts65Dn (trisomic) mice were selected. Two independent reviewers reviewed the articles with selective inclusion criteria using a standard data extraction form. Cell therapy showed no significant findings on the physical appearance, cognitive function, social, and behavior skills of DS patients. Interestingly, implantation of murine neural stem cell (mNSC) or murine neural progenitor cell (mNPC) showed better cell survival and response towards brain injury, decrease tau + granules and increase granules density in the dentate gyrus in the trisomic mice. mNSC/mNPC in mice brain was found to be able to migrate to the sites of the injury following chemokine signals and eventually provide neuroprotection and promote axonal growth. To conclude, mNSC/mNPC implantation could be considered as an alternative treatment for DS or DS with early onset of Alzheimer Disease (AD).

The possible effect of microRNA-155 (miR-155) and BACE1 inhibitors in the memory of patients with down syndrome and Alzheimer's disease: Design, synthesis, virtual screening, molecular modeling and biological evaluations

MiR-155 plays main roles in several physiological and pathological mechanisms, such as Down syndrome (DS), immunity and inflammation and potential anti-AD therapeutic target. The miR-155 is one of the overexpressed miRNAs in DS patients that contribute directly and indirectly to the onset or progression of the DS. Since the miR-155 can simultaneously reduce the translation of several genes at post-transcriptional levels, targeting the miR-155 might set the stage for the treatment of DS. One of the rational strategies in providing therapeutic interventions in this respect is to design and develop novel small molecules inhibiting the miR-155 function or biogenesis or maturation. In the present study, we aim to introduce small molecule compounds with the potential to inhibit the generation of the selectively miR-155 processing by employing computational drug design approaches, as well as in vitro studies. We designed and synthesized a novel series of imidazo[1,2-a]pyridines derivatives as new nonpeptic candidates for the treatment of DS with AD. The designed compounds were investigated for their BACE1 and miR-155 binder inhibitory potential in vitro and in cell. In addition, we present a systematic computational approach that includes 3 D modeling, docking-based virtual screening, and molecular dynamics simulation to identify Small - molecule inhibitors of pre-miR-155 maturation. To confirm the inhibitory potential of compound 8k on miR-155 maturation, qRT- PCR was performed. All our results confirm that compound 8k, in addition to being a good inhibitor of BACE1, can also be a good inhibitor of miR-155. Communicated by Ramaswamy H. Sarma

From the lab to the people: major challenges in the biological treatment of Down syndrome.

Down syndrome (DS) refers to a genetic condition due to the triplication of human chromosome 21. It is the most frequent autosomal trisomy. In recent years, experimental work has been conducted with the aim of removing or silencing the extra chromosome 21 (C21) in cells and normalizing genetic expression. This paper examines the feasibility of the move from laboratory studies to biologically treating “bone and flesh” people with DS. A chromosome or a gene therapy for humans is fraught with practical and ethical difficulties. To prevent DS completely, genome editing would have to be performed early on embryos in the womb. New in vitro findings point toward the possibility of epigenetic silencing the extra C21 in later embryonic or fetal life, or even postnatally for some aspects of neurogenesis. These possibilities are far beyond what is possible or allowed today. Another approach is through epigenetic regulation of the overexpression of particular genes in C21. Research with mouse modeling of DS is yielding promising results. Human applications have barely begun and are questioned on ethical grounds.

Treating acute myeloid leukemia among children with down syndrome

Abstract Background: Down Syndrome (DS) children with acute myeloid leukemia (AML) have unique differences in clinical features, epidemiologic nature, and biologic patterns of disease compared with AML in children without DS. Aims and Objective: AML in DS children should be considered distinct disorder from AML in Non DS population and treatment needs to be customized for this population. In this retrospective study spanning from 2014 to 2019 we present our experience of managing leukemia in children with DS. Materials and Methods: From 2014 and 2019, 72 children aged below 18 years were managed at our institute with acute myeloid leukemia (AML). Out of these 72 children with AML, 7 children were with DS which was confirmed by karyotyping. Majority of these children had M7 while M2 and M4 subtypes were seen in one child each. On conventional karyotyping in addition to trisomy 21 additional cytogenetic abnormalities were seen in 4 patients. Two children had trisomy 8. One child had deletion of 11 chromosomes and one had translocation between 8 and 21 chromosomes. Results: All 7 children were administered intensive chemotherapy with curative intent after informed parental consent. All 7 children achieved complete remission. Four out of 7 children had complications related to severe neutropenia. Conclusion: All patients of DS with AML should be offered chemotherapy with curative intent. Endeavour should be to give less aggressive chemotherapy protocol to bring down treatment related mortality.

Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial

This single center, randomized, double-blind, placebo-controlled phase 3 study investigated the effects of levothyroxine, folic acid, or both in combination over 12 months on global development in 143 infants with Down syndrome (DS). Over the last decades, treatment of DS associated co-morbidities has improved their life-expectancy. However, a therapy to improve mental development is still lacking. Folic acid as well as thyroxine are both crucial for normal neurodevelopment in utero and postnatally. Previously, two randomized controlled studies suggested beneficial effects of either folic acid especially in children treated with levothyroxine in an age group of 3–30 months [1] and levothyroxine alone started in the neonatal period [2], while a short-term cross-over study did not observe effects of levothyroxine on cognitive function in DS patients [3].

54.4 DOWN SYNDROME

Mental health disorders occur in Down syndrome (DS) at a greater incidence as compared with the typically developing population. As a result of diagnostic overshadowing, differences in clinical presentation of symptoms, and limited research, significant challenges can arise in the mental health assessment, diagnosis, and treatment of DS. This session will focus on the mental health assessment, diagnosis, and treatment of common mental health disorders in DS.

Pharmacotherapy of Down's Syndrome: When and Which?

Down Syndrome (DS) is an essential genetic disease that involves many other body systems along with cerebral functions. The postnatal approach to treat this genetic disease includes intervention on various related disorders (e.g., heart failure, respiratory, oral, ear, and hearing disorders). However, different proposed treatments do not significantly improve the quality of life of these subjects. Another approach to the treatment of DS considering the possibility to intervene on the embryo was recently introduced. As of this, the current study has reviewed different outcomes regarding DS treatment in an animal model, namely the Ts65Dn mouse. The obtained results encouraged spending more time, efforts, and resources in this field. Besides, various treatment strategies were tried to include genetic modification, treatment with vasoactive intestinal peptide derivatives or fluoxetine. However, the main obstacle to the use of these possible treatments is the ethical issues it raises. The progression of the pregnancy in spite of awareness that DS affects the unborn and prenatal treatment of DS injured embryo are relevant dilemmas. Thus, talented researchers should spend more efforts to improve the quality of life for people affected by DS, which will allow probably a better approach to the ethical issues.

Down Presymptomatic View of Dementia Characteristics

Down syndrome (DS) is caused by complete or segmental chromosome 21 trisomy that results in neurodegeneration and progressive intellectual disability. Abnormal function in the prefrontal cortex, cerebellum, and hippocampus are the main reasons for cognitive deficits in DS that result in impaired cognitive function, delayed speech and language, learning and memory disability, and behavioral and emotional disorders. There is no specific treatment for DS, and our understanding of the mechanisms of the disorder is incomplete and causes to hamper the development of effective therapies regarding the development of neuropathology and memory loss in DS. Here, we review the literature on cognitive functioning, unique characteristics, environmental considerations, and recent findings on Alzheimer’s disease in DS.

Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome

Down syndrome is the most common genetic cause of intellectual disability and occurs due to the trisomy of human chromosome 21. Adolescent and adult brains from humans with Down syndrome exhibit various neurological phenotypes including a reduction in the size of the corpus callosum, hippocampal commissure and anterior commissure. However, it is unclear when and how these interhemispheric connectivity defects arise. Using the Ts65Dn mouse model of Down syndrome, we examined interhemispheric connectivity in postnatal day 0 (P0) Ts65Dn mouse brains. We find that there is no change in the volume of the corpus callosum or anterior commissure in P0 Ts65Dn mice. However, the volume of the hippocampal commissure is significantly reduced in P0 Ts65Dn mice, and this may contribute to the impaired learning and memory phenotype of this disorder. Interhemispheric connectivity defects that arise during development may be due to disrupted axon growth. In line with this, we find that developing hippocampal neurons display reduced axon length in vitro, as compared to neurons from their euploid littermates. This study is the first to report the presence of defective interhemispheric connectivity at the time of birth in Ts65Dn mice, providing evidence that early therapeutic intervention may be an effective time window for the treatment of Down syndrome.

P.078 Clinical trials in children with Down Syndrome: now and future

Background: Down syndrome (DS) is the most common genetic cause of intellectual disability.Although progress in managing co-morbidities has improved life expectancy, no therapeutic options have showed to significantly improve intellectual deficiencies.The current focus of the pharmacological treatment of DS is on the improvement of the cognitive impairment that is probably due to neurodevelopmental alterations,neurotransmitter alterations and neurodegeneration,and is also targeted to the overexpression of selected genes on HSA21. Methods: We review the clinical trials of the last 5 years focusing on the cognitive improvement of children with DS. Results: We report the results of therapeutic trials concerning selective negative allosteric regulators of the GABAAa5 receptor, NMDA antagonists, Kinase inhibitors of DYRK1A, folinic acid and thyroid hormone supplementation, activators of serotonergic and cholinergic system. Conclusions: The incomplete understanding of individual phenotypic variability, natural history, lack of biomarkers, no adapted neuropsychological tests, placebo effect, epigenetic effect have limited our capacity to succeed, even when promising drugs are tested.We need new tools and models will allow a better understanding of the pathophysiology. We also need to create more sensitive and realistic outcome mesures to quantify disease and therapeutic efficacy. The association of different therapeutic agents (epidrugs included) with cognitive stimulation could be a future strategy.