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The INCLUDE Project Research Plan
(INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndrome)
NIH seeks public input on research goals and objectives for revising and updating its research plans on Down syndrome. The Request for Information invites the public to provide feedback via email to DownSyndrome@mail.nih.gov through July 10, 2020.
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Down syndrome is the most common genetic cause of intellectual disability, the most common autosomal trisomy, and one of the most visible and universally recognized genetic syndromes. Each year there are approximately 5300 babies born in the United States with Down syndrome. Within the past 25 years, the average lifespan for a person with Down syndrome has doubled, from 30 to 60 years. Despite this increase in lifespan, individuals with Down syndrome and their families face significant and changing health challenges.
Fiscal Year 2018 Omnibus Appropriations Report stated the following:
“Down syndrome. The agreement directs the NIH Director to develop a new trans-NIH initiative – involving, at a minimum, NICHD, NIA, and NCI – to study trisomy 21, with the aim of yielding scientific discoveries to improve the health and neurodevelopment of individuals with Down syndrome and typical individuals at risk for Alzheimer's disease, cancer, cardiovascular disease, immune system dysregulation, and autism, among others. This initiative shall bring together research results that will be available to academic researchers, nonprofit organizations, and industry researchers. Funding for this trans-NIH initiative will supplement, not supplant, existing NIH funding levels for Down syndrome research.”
This legislation provides NIH with the opportunity to not only expand its current efforts on Down syndrome and commonly co-occurring conditions in individuals with Down syndrome that are also seen in the general population, such as Alzheimer’s disease/dementia, autism, cataracts, celiac disease, congenital heart disease, diabetes, and immune system dysregulation, but to build an integrated effort across NIH that will be truly transformative in these areas. A series of engagement efforts with all stakeholders will inform INCLUDE and ensure all needed resources and expertise are utilized. A series of scientific workshops engaging the relevant research and family communities will be held in late FY2018 and early FY2019 to further inform this effort, which are further described below.
Following collaborative discussions across its institutes and centers, NIH has identified three major components for a trans-NIH effort on Down syndrome (INCLUDE), spanning basic to clinical research:
(1) targeted high risk - high reward basic science studies;
(2) development of a cohort to perform deep phenotyping and study co-existing conditions; and
(3) establishing a clinical trials network so that therapies for co-occurring conditions can begin to be tested in the Down syndrome population as soon as possible, while also further supporting and expanding existing clinical trial infrastructure.
An enhanced understanding of the constellation of co-occurring conditions and resiliencies in individuals with Down syndrome will yield a unique opportunity to both address the unmet health needs of individuals with Down syndrome while simultaneously improving the health of all individuals.
The INCLUDE research plan for FY2018 and beyond is further described below.
INCLUDE will focus on Down syndrome, to improve the health and well-being of individuals with Down syndrome, and also to learn about risk and resilience factors for common diseases that they share with individuals who do not have Down syndrome. Down syndrome is associated with intellectual challenges, an increased prevalence of autism (10-18%) and epilepsy (1-13%), and Hirschsprung’s disease. About 75% of individuals experience cognitive decline in a syndrome that resembles Alzheimer’s disease, but has its onset a decade or two earlier than typical Alzheimer’s disease. Individuals with Down syndrome also have high rates of hearing loss (up to 75%), eye abnormalities (60%), congenital heart defects (~50%), sleep apnea (50%), pulmonary hypertension (~10%, which is significantly higher than in the general population), gastrointestinal malformations (12%), thyroid disease (4-18%), leukemia (1%), and other autoimmune disorders including celiac disease (5%). However, people with Down syndrome infrequently develop solid tumors such as breast or prostate cancer, and despite multiple risk factors for coronary artery disease and high rates of obesity, sleep apnea, and type 1 diabetes, they rarely develop atherosclerosis or have myocardial infarctions. Understanding the molecular basis of this unique combination of risk and resiliencies will inform medical advances for individuals with Down syndrome, and for individuals who do not have Down syndrome but share these co-occurring conditions.
Furthermore, despite increases in lifespan among individuals with Down syndrome, opportunities for them to participate in medication trials have been hampered by difficulties in recruiting large enough clinical cohorts, limited knowledge of appropriate endpoints and outcome measures for this population, lack of stratification to identify positive responses to the medication above placebo effects, and lack of resources to sustain a clinical trials program for the long-term that would allow new therapeutics to be tested. The few trials conducted to date have generally enrolled adults or adolescents who may be outside the window of neuroplasticity that would allow for cognitive benefit.
“Down Syndrome Directions: NIH Research Plan on Down Syndrome,” updated in 2014, highlighted many research objectives and opportunities, and added a new section on aging. The research plan advocated for greater understanding of commonly co-occurring conditions in individuals with Down syndrome that are also seen in the general population, such as Alzheimer’s disease/dementia, autism, cataracts, celiac disease, congenital heart disease, diabetes, increased susceptibility to mucosal and respiratory infections, and immune system dysregulation to improve the health of those with Down syndrome and all individuals who share these conditions. The plan also recommended additional study of common complications of aging, such as coronary heart disease and solid cancers, which are rarely seen in individuals with Down syndrome. More recent discoveries have enhanced our understanding of chromosome segregation and chromosome silencing, identified certain proteins and neurotropic factors involved in brain development using mouse models, and uncovered the role of interferons in immune dysregulation, each of which has the potential to lead to development of novel therapies for individuals with Down syndrome, as well as broader applications. People with Down syndrome are often excluded from clinical research, such as trials of potentially beneficial drugs and therapeutics that are used to treat the same condition in the general population. There would be great value in connecting people with Down syndrome to therapies that could improve their overall health and quality of life.
Experience from NICHD’s “DS-Connect®: The Down Syndrome Registry,” an online survey tool that introduces individuals with Down syndrome and their families to research opportunities, suggests that there is great interest in participating in clinical studies. Opportunities to engage the Down syndrome community in research are also facilitated by the members of the Down Syndrome Consortium, a public-private partnership involving NIH Institutes and Centers, advocacy groups, private foundations and professional organizations, and self-advocates and families, all sharing a passion for promoting research that will benefit people with Down syndrome.
Addressing the needs and inroads outlined above, INCLUDE will build a comprehensive, trans-NIH strategy to address critical health and quality-of-life needs for individuals with Down syndrome, leveraging the full range of resources across NIH to bring results rapidly to individuals with Down syndrome and their families. The main goals are to accelerate the development of new therapies, while simultaneously bringing promising agents already in development to individuals with Down syndrome as quickly as possible. Generation of a complete molecular snapshot of Down syndrome will unmask promising new targets, while targeted investments to agents on the cusp of clinical development will speed their translation. At the same time, full inclusion of individuals with Down syndrome into ongoing clinical trials will ensure that they will reap the benefits of agents already in development. A clinical trials network will be developed to engage individuals with Down syndrome where they may already receive health care, thus creating a “medical home” for these individuals and their families as they endeavor to manage multiple health needs. Such a resource will also ensure that new therapies can be brought to trial as they emerge in the future. A series of scientific workshops engaging the relevant research and family communities will be held in late FY2018 and early FY2019 to further inform this effort, which are further described below.
Noting the involvement of multiple organ systems in Down syndrome and its co-occurring conditions, this effort will appropriately take advantage of the full range of existing resources across NIH, integrating the expertise of at least eighteen NIH institutes and centers, including the National Cancer Institute (NCI), National Eye Institute (NEI), National Heart, Lung, and Blood Institute (NHLBI), National Human Genome Research Institute (NHGRI), National Institute on Aging (NIA), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute on Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Environmental Health Sciences (NIEHS), National Institute of General Medical Sciences (NIGMS), National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Nursing Research (NINR), National Institute on Minority Health and Health Disparities (NIMHD), National Center for Complementary and Integrative Health (NCCIH), and the National Center for Advancing Translational Sciences (NCATS).
A comprehensive clinical cohort study with deep phenotyping and exploration of pan-‘omics (e.g. genomics, transcriptomics) would permit identification of biomarkers and outcomes for the co-occurring conditions in Down syndrome. Coupled with development of a clinical trials readiness program, and informed by basic science discoveries, this combination of resources could have a great impact on addressing health disparities that exist for people with Down syndrome and could also lead to the development of therapies to improve outcomes for those with and without the condition.
Therefore, INCLUDE will have three major components:
Component 1: Targeted, high risk - high reward, basic science studies
Research over the past several decades has elucidated the roles of individual genes in the Down syndrome critical region on chromosome 21 and has provided insight about their roles in cognition and/or neurodegeneration. Today, it is possible to examine the roles of multiple genes on chromosome 21 simultaneously in several model systems. Topics of emphasis may include: chromosome silencing, immune system dysregulation, epigenetic/metabolomic/transcriptomic profiling in model organisms/iPSCs (induced pluripotent stem cells)/brain organoids, development of novel model systems, and development of a molecular atlas for cardiac and other specimens. Promising leads in these areas will be further supported to speed clinical development, with an emphasis on those that can inform the other two components, namely a cohort study and a clinical trials network.
Component 2: Cohort Study to connect existing resources and expand to inclusion of individuals with Down Syndrome
A large cohort of individuals with Down syndrome is essential to follow individuals’ development over time and perform deep phenotyping and natural history studies. INCLUDE will develop a comprehensive genomic, epigenomic, transcriptomic, and proteomic map to help understand the predisposing risk and protective factors that underlie the highly penetrant features in Down syndrome. Enrolling a cross-sectional cohort of individuals with Down syndrome at different ages across the lifespan will capture the broadest array of phenotypes and ages of onset for the co-existing conditions, as well as the critical windows for interventions.
We have an unprecedented opportunity to link together several existing cohorts, registries, and other data sources to produce a comprehensive precision medicine platform for Down syndrome across the lifespan. A unified cohort could also provide a platform for testing mobile health technologies, as well as for clinical trials.
The Guiding Principles for such a project would include full data sharing with appropriate privacy protections, adherence to the “FAIR” principles (Findable, Accessible, Interoperable, and Reusable) in concordance with the NIH Data Commons, and representation by engaged parties including individuals impacted by Down syndrome, and consider options for return of results to participants from the onset.
Component 3: Clinical trials network to create a “medical home” for individuals with Down Syndrome and encourage their inclusion into ongoing clinical research
As mentioned above, despite the relative frequency of Down syndrome in the population, very few, if any clinical studies have examined differences in how commonly used medications affect people with Down syndrome. The extremely limited number of medication trials to date in humans with Down syndrome (11 worldwide) have primarily focused on improving cognition, memory and adaptive functioning. There has been a remarkable lack of success in these clinical trials1,2. Though it is possible that none of the medications tested had the appropriate properties to provide benefit, other explanations for failure of these trials include the fact that they may have been underpowered (no trial has had more than 129 subjects with Down syndrome), they involved adolescents or adults (with reduced brain plasticity), or a placebo effect could have produced improvements in the control groups3.
Establishment of a clinical trials network would focus on repurposing existing therapies as well as developing new ones. When appropriate, existing clinical trials infrastructures will also be used to further these important objectives. These clinical research efforts will also entail development of clinical measures that are meaningful for individuals with Down syndrome to ensure that efficacious therapies come to fruition. In addition, these efforts will target quality-of-life challenges that individuals with Down syndrome and their families confront across the lifespan, such as early interventions at critical stages of neurodevelopment and novel therapies for Alzheimer's disease that develops in individuals with Down syndrome later in life. This initiative will serve as the test case to articulate the goals of full inclusion of persons with intellectual disabilities, specifically Down syndrome, in research, and will develop the standards for inclusivity for this population previously ignored by, if not explicitly excluded from, clinical research.
We plan to invest $21M in FY2018 to lay critical groundwork and engage the scientific community, judiciously spending FY2018 funds by supplementing the most promising existing basic science awards and contracts, cohort studies, or clinical trial network, to jumpstart this effort while setting the stage for FY2019 and beyond. Specifically, we will solicit administrative supplement applications via two notices:
- Notice for existing studies in Down syndrome that can be supplemented to address a targeted area of emphasis, expand the sample size, address a related issue of relevance for Down syndrome research, or create an expanded resource or cohort that will pave the way for future cohorts and clinical trials
- Notice to amend or augment existing projects that are not focused on Down syndrome by adding a cohort or aim that includes a Down syndrome component.
Following programmatic review at each institute and coordination among all participating institutes, a final funding plan for administrative supplements for FY2018 will be decided by the NIH Director. Several scientific workshops are planned for late FY2018/early FY2019 to engage with all relevant research communities as planning for INCLUDE continues, which are further described below.
Following an initial investment of $22 million in FY 2018 to build capacity and plan for the INCLUDE project, additional funding was made available by Congress for FY 2019 to fully launch INCLUDE.* This support will continue FY2018 out-year commitments/ongoing obligations and also support additional supplements in FY2019 to further leverage existing infrastructure. In FY2019, we will also transition the funding stream to one driven by new Requests for Applications (RFAs) to the greatest extent possible. We anticipate that this level of support will be maintained in FY2020 through FY2022 as this effort is fully underway, supporting the out-years of the main components. Additional scientific workshops are planned for FY2019 and FY2020 in order to ensure that the scientific goals of INCLUDE are continually informed by the research community and all stakeholders to produce meaningful results for individuals with Down syndrome and their families, as further described below.
*Total FY2019 funding for INCLUDE is currently being finalized. Previously stated amounts were funding estimates pending availability of funds.
Several workshops are planned for late FY2018/early FY2019 to engage with all relevant scientific and clinical research expertise, individuals with Down syndrome, their families and caregivers, the broader Down syndrome community, and industry partners as planning for INCLUDE continues. These workshops will focus on the main components of INCLUDE, particularly on development of a cohort of individuals with Down syndrome across the lifespan and on the current state of the science for development of clinical trials.
Subsequent workshops are planned for FY2019 and FY2020 to ensure that the scientific goals of INCLUDE are continually informed by the research community and all stakeholders to produce meaningful results for individuals with Down syndrome and their families. These workshops will focus on understanding resiliencies in Down syndrome and on the planning of clinical trials. Workshops in FY2021 will take stock of the status of the cohort studies and clinical trials and make appropriate adjustments as needed, anticipating the need for novel treatment development and trials in Down syndrome as INCLUDE resources are fully developed.
Appropriate to the multi-organ system nature of Down syndrome and its co-occurring conditions, and in a truly trans-NIH effort, we have assembled a team across NIH to fully meet this compelling opportunity, leveraging the expertise and resources of eighteen NIH Institutes and Centers. We have assembled a steering committee to guide this effort. Dr. Lawrence Tabak, NIH Principal Deputy Director, will chair this committee in partnership with Dr. Diana Bianchi, Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and Dr. Gary Gibbons, Director, National Heart, Lung, and Blood Institute (NHLBI) as co-chairs. The other participating institutes with significant involvement in this project will also be represented on this steering committee, including the National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of General Medical Sciences (NIGMS), and the National Institute on Aging (NIA). This steering committee will be complemented by the Trans-NIH Down Syndrome Working Group, that has already embarked on collaborative efforts to address Down syndrome, and which has membership from the National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Human Genome Research Institute (NHGRI), National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Aging (NIA), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute on Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute on Minority Health and Health Disparities (NIMHD).
Through INCLUDE, we aim to support the most promising high risk-high reward basic science. In addition, development and maintenance of a data and sample repository will serve the scientific community – both Down syndrome researchers and those who focus on the co-occurring conditions – for decades to come. Individuals with Down syndrome will be encouraged to participate in ongoing clinical research studies, while a clinical trial network and “medical home” will be created for individuals with Down syndrome and their families to ensure full inclusion into promising clinical research as novel therapies emerge in the future. We welcome the opportunity to embark on this initiative in partnership with the Down syndrome community to improve the health and quality-of-life of individuals with Down syndrome, and all individuals who are impacted by many of these co-occurring conditions.
 Keeling et al. (2017). Challenges in measuring the effects of pharmacological interventions on cognitive and adaptive functioning in individuals with Down syndrome: A systematic review. Am J Med Genet 173A:3058-66.
This page last reviewed on April 15, 2020