Periodic Reporting for period 2 - GO-DS21 (Gene overdosage and comorbidities during the early lifetime in Down Syndrome)
Berichtszeitraum: 2021-07-01 bis 2022-12-31
The aim of the project is to elucidate etiological mechanisms involved in the appearance of obesity, and
intellectual disability (ID) comorbidities in Down syndrome (DS). With its incidence of 1 in 1000 births,
DS offers a great opportunity to uncover common/novel mechanisms because it is associated with a
higher risk to develop severe obesity and ID. The increased risk to develop this combination of
comorbidities in DS, suggests that specific genetic or epigenetic mechanisms associated with trisomy
21 (the cause of DS) predispose to this comorbidity.
For this aim, GO-DS21 will have the following objectives: 1) To determine age-related comorbidity patterns observed over the early lifetime (before age 45) in persons with Down syndrome. 2) To identify specific physiological biomarkers, and regulatory and epigenetic signatures in human, cellular and
animal models. 3) To decipher the contribution of environmental factors (stress, diet, exercise) to trisomy 21 obesity/ID comorbidities in preclinical models. 4) To investigate the effects of overdosage of three
candidate genes to explain comorbid patterns in mouse models. 5) To integrate multilevel data from human patients, preclinical and cellular models across different spatial and temporal scales of biological
complexity using computational biology models and machine learning approaches. 6) To design new therapeutic interventions to reduce the penetrance of comorbidities in preclinical models. This approach will help to improve diagnosis and understanding of prognostic factors and will establish recommendations and targeted interventions to prevent or minimise comorbidities in persons with DS.
Beyond the impact for patients with DS we expect that the findings of this project will also be beneficial
for the general population.
intellectual disability (ID) comorbidities in Down syndrome (DS). With its incidence of 1 in 1000 births,
DS offers a great opportunity to uncover common/novel mechanisms because it is associated with a
higher risk to develop severe obesity and ID. The increased risk to develop this combination of
comorbidities in DS, suggests that specific genetic or epigenetic mechanisms associated with trisomy
21 (the cause of DS) predispose to this comorbidity.
For this aim, GO-DS21 will have the following objectives: 1) To determine age-related comorbidity patterns observed over the early lifetime (before age 45) in persons with Down syndrome. 2) To identify specific physiological biomarkers, and regulatory and epigenetic signatures in human, cellular and
animal models. 3) To decipher the contribution of environmental factors (stress, diet, exercise) to trisomy 21 obesity/ID comorbidities in preclinical models. 4) To investigate the effects of overdosage of three
candidate genes to explain comorbid patterns in mouse models. 5) To integrate multilevel data from human patients, preclinical and cellular models across different spatial and temporal scales of biological
complexity using computational biology models and machine learning approaches. 6) To design new therapeutic interventions to reduce the penetrance of comorbidities in preclinical models. This approach will help to improve diagnosis and understanding of prognostic factors and will establish recommendations and targeted interventions to prevent or minimise comorbidities in persons with DS.
Beyond the impact for patients with DS we expect that the findings of this project will also be beneficial
for the general population.
During this reporting period, We have made some progress on different targets. First, we have additional knowledge about comorbidity patterns seen during the early lifetime (before 45
years) in persons with DS. DS individuals have been identified from UK electronic health records and matched with controls from Clinical Practice Research Datalink (CPRD), and a paper has been published on diabetes and its relationship with obesity in people with DS (doi:10.2337/dc22-0482).
Another paper on other comorbidities has been submitted and is under review. We have set up the eCRF, drafted and signed the Data Management Plan, as well as Material and Transfer Agreements.
We have engaged with different participant recruitment centres from Primary and Secondary care, as well as charities and associations. In total, we have seen 121 participants (40% of target) for the baseline
visit and have followed up 48 (80% of target) of them for at the phenotyping visit. We have also sent all necessary PBMC samples for iPSC reprogrammation. We have also alerted the community about the susceptibility to Covid-19, clinical presentation, severity, and treatment of COVID-19 in people wih DS
(DOI: 10.1007/s11606-022-07420-9; 10.3390/jcm10215125; 10.1016/j.eclinm.2021.100769; 10.3390/jcm10163748; 10.1136/bmjopen-2021-052482; 10.3390/vaccines10040530;
10.7189/jogh.12.05035).
Second, we have evaluated the contribution of environmental factors to DS comorbidities. We have defined and implemented a unique standardized pipeline for studying comorbidities in the selected
Dp(16)1Yey DS mouse model. We have combined a pipeline with diet induced obesity and a very specific metabolic and cognitive test battery. Conditions to analyse further comorbidities in DS models for addressing the impact of HPA dysregulation, and excessive glucocorticoids have been defined. Two
more specific pipelines to address the role of stress and exercise on DS comorbidities in the Dp(16)1Yey model have been set up. Progress to dissect the genetic factors and to explore the changes at molecular/cellular and/or biomarker levels is ongoing (10.1007/s00335-020-09839-z; 10.1038/s41598-
020-72625-z; 10.3389/fnins.2020.00670; 10.1093/hmg/ddab012; 10.3389/fnbeh.2021.772734; 10.21203/rs.3.rs-1158032/v1; 10.3389/fnmol.2021.664912; 10.1242/dmm.049721). We have also observed new comorbidities in DS animal models that reminds some of the comorbidities associated with DS in human, such as increased lethality due to aneuploidy and ventriculomegaly. Third, the partners of this project have worked together to finalise the full-DS comorbid pipeline and share obesity and cognitive phenotyping protocols and expertise. Duplication overexpressing candidate genes mouse models were obtained and validated. All the colonies of mice are established at the relevant partner institutes. Preliminary studies on the impact of one candidate overexpression on metabolism and cognition have been performed (DOI: 10.3390/ijms22116047; 10.3390/genes12111833; 10.14283/jpad.2022.18; 10.3390/ph14111086; 10.1101/2021.05.01.442242; 10.1021/acs.jmedchem.1c01141; 10.1021/acs.jmedchem.2c02068). This includes the assessment of food preference and caloric intake in mutant compared to wild-type animals. Compounds targeting
candidates have been shared. Three new compounds have been tested and validated on mouse and rat models.Fourth partners have finalized and shared the protocols for sampling blood for metabolomic, epigenomic, proteomic and microbiota analysis. Platforms have provided the clinical sites with specific tubes when necessary. The three clinical sites have started sending samples for the pilot studies. Buffy coats have been sent for producing iPSC from patients included in GO-DS21. The second attempt
allowed the reprogrammation of blood cells from two buffy coats of iPS clones from 8 individuals with DS (4 males & 4 females) with high and low BMI. Several discussions and pilots have been set up to achieve this objective to integrate various type of data from human and preclinical model. We are on a
good track to be able to start the work and reach our objective in the years to come.
years) in persons with DS. DS individuals have been identified from UK electronic health records and matched with controls from Clinical Practice Research Datalink (CPRD), and a paper has been published on diabetes and its relationship with obesity in people with DS (doi:10.2337/dc22-0482).
Another paper on other comorbidities has been submitted and is under review. We have set up the eCRF, drafted and signed the Data Management Plan, as well as Material and Transfer Agreements.
We have engaged with different participant recruitment centres from Primary and Secondary care, as well as charities and associations. In total, we have seen 121 participants (40% of target) for the baseline
visit and have followed up 48 (80% of target) of them for at the phenotyping visit. We have also sent all necessary PBMC samples for iPSC reprogrammation. We have also alerted the community about the susceptibility to Covid-19, clinical presentation, severity, and treatment of COVID-19 in people wih DS
(DOI: 10.1007/s11606-022-07420-9; 10.3390/jcm10215125; 10.1016/j.eclinm.2021.100769; 10.3390/jcm10163748; 10.1136/bmjopen-2021-052482; 10.3390/vaccines10040530;
10.7189/jogh.12.05035).
Second, we have evaluated the contribution of environmental factors to DS comorbidities. We have defined and implemented a unique standardized pipeline for studying comorbidities in the selected
Dp(16)1Yey DS mouse model. We have combined a pipeline with diet induced obesity and a very specific metabolic and cognitive test battery. Conditions to analyse further comorbidities in DS models for addressing the impact of HPA dysregulation, and excessive glucocorticoids have been defined. Two
more specific pipelines to address the role of stress and exercise on DS comorbidities in the Dp(16)1Yey model have been set up. Progress to dissect the genetic factors and to explore the changes at molecular/cellular and/or biomarker levels is ongoing (10.1007/s00335-020-09839-z; 10.1038/s41598-
020-72625-z; 10.3389/fnins.2020.00670; 10.1093/hmg/ddab012; 10.3389/fnbeh.2021.772734; 10.21203/rs.3.rs-1158032/v1; 10.3389/fnmol.2021.664912; 10.1242/dmm.049721). We have also observed new comorbidities in DS animal models that reminds some of the comorbidities associated with DS in human, such as increased lethality due to aneuploidy and ventriculomegaly. Third, the partners of this project have worked together to finalise the full-DS comorbid pipeline and share obesity and cognitive phenotyping protocols and expertise. Duplication overexpressing candidate genes mouse models were obtained and validated. All the colonies of mice are established at the relevant partner institutes. Preliminary studies on the impact of one candidate overexpression on metabolism and cognition have been performed (DOI: 10.3390/ijms22116047; 10.3390/genes12111833; 10.14283/jpad.2022.18; 10.3390/ph14111086; 10.1101/2021.05.01.442242; 10.1021/acs.jmedchem.1c01141; 10.1021/acs.jmedchem.2c02068). This includes the assessment of food preference and caloric intake in mutant compared to wild-type animals. Compounds targeting
candidates have been shared. Three new compounds have been tested and validated on mouse and rat models.Fourth partners have finalized and shared the protocols for sampling blood for metabolomic, epigenomic, proteomic and microbiota analysis. Platforms have provided the clinical sites with specific tubes when necessary. The three clinical sites have started sending samples for the pilot studies. Buffy coats have been sent for producing iPSC from patients included in GO-DS21. The second attempt
allowed the reprogrammation of blood cells from two buffy coats of iPS clones from 8 individuals with DS (4 males & 4 females) with high and low BMI. Several discussions and pilots have been set up to achieve this objective to integrate various type of data from human and preclinical model. We are on a
good track to be able to start the work and reach our objective in the years to come.
Overall, despite several delays due to the Covid-19 pandemic, we have validated some new drugs that are promising for treating intellectual deficits in DS and may be of interest for the attached comorbidities (DOI: 10.3390/ijms22116047; 10.3390/genes12111833; 10.14283/jpad.2022.18; 10.3390/ph14111086;
10.1101/2021.05.01.442242). The information about GO-DS21 are available from the project website (www.go-ds21.eu) as well as project brochures in three languages and a Twitter account. The GODS21 partners organised and attended several virtual conferences where they presented the GO-DS21
project and first results. Furthermore, the GO-DS21 partners have used their strength to work and report on the higher sensitivity of people with DS to Covid-19 leading to two publications. This has helped to raise awareness about DS and Covid-19 infection in the society and help some countries to prioritise
the DS population to vaccination and care.
10.1101/2021.05.01.442242). The information about GO-DS21 are available from the project website (www.go-ds21.eu) as well as project brochures in three languages and a Twitter account. The GODS21 partners organised and attended several virtual conferences where they presented the GO-DS21
project and first results. Furthermore, the GO-DS21 partners have used their strength to work and report on the higher sensitivity of people with DS to Covid-19 leading to two publications. This has helped to raise awareness about DS and Covid-19 infection in the society and help some countries to prioritise
the DS population to vaccination and care.