2016-2017 Research Grant Awards

The LuMind Research Down Syndrome Foundation announces the award of $1,615,000 in funding for seven new Research Grants, propelling Down syndrome cognition research. The latest recipients of LuMind RDS Foundation grant funding are researchers at Johns Hopkins School of Medicine, Emory University School of Medicine, University of California San Diego School of Medicine, University of Arizona, Stanford University, Palo Alto Veterans Research Institute/VA Palo Alto Health Care System, and AC Immune, a biopharmaceutical company.

LuMind RDS Foundation has awarded more than $15 million in research grants since our founding in 2004.

Johns Hopkins University School of Medicine – A Down Syndrome Center for Fundamental Research-Cognition

$250,000 RESEARCH CENTER GRANT AWARDED TO DR. ROGER REEVES, PRINCIPAL INVESTIGATOR, AND CO- PRINCIPAL INVESTIGATORS DRS. DAVID FOSTER AND PAUL WORLEY.

Significant progress has been made in the past year as projects have matured and significant new collaborations have been established to drive additional new research advances. The Worley lab work with mis-regulated expression of the pentraxin NPTX2, a synaptic protein encoded by a non-chromosome 21 gene, in Ds and AD and has identified what appears to be a robust potential biomarker of AD onset in Ds brains. The proposed research will analyze this potential biomarker in additional brain tissue and CSF from people with Ds who are showing cognitive decline. The CSF samples will be provided through new collaboration with researchers involved in the NIH-supported AD Biomarkers in DS initiative. The Foster lab continues their collaboration with Dr. M.-C. Potier (ICM, France) investigating the fundamental basis for differences in neural transmission in trisomic mouse models using a novel electrophysiological technique that supports rapid, real-time assessment of the processes that underlie learning and memory. This represents a new potential key approach for assessment of cognitive function and rapid drug screening, and additionally for characterization of a new Ds mouse model from a third renewed collaboration of the Reeves lab with Dr. M. Oshimura (Tottori University, Japan) who has created a new mouse model of trisomy 21, MAC21q. This mouse model contains the entire long arm of human chr21 (which includes nearly all of the genes on the chromosome) in a freely segregating mouse artificial chromosome which appears to be retained in essentially all cells. Characterization of neural anatomy and function in these MAC21q mice will be an important new goal of all three labs. Proposed research in the projects will: 1) Further investigate the role of NPTX2 down-regulation in Ds in abnormal synaptic transmission and how this may alter excitatory-inhibitory balance and the development of the AD pathology in humans and mouse model, and potentially whether measurements of NPTX2 can serve as a biomarker; 2) Further assess the novel electrophysiological (EP) method for real-time detection of hippocampal neural circuit/network dysfunction and pharmacological-mediated changes related to cognition; and, 3) Further investigate the mechanistic basis by which treatment with SAG, early in life of a mouse model of Ds restores cerebellar and hippocampal structure and function involving learning and memory and potential for clinical translation; and, 4) Characterization of a new next generation mouse model for trisomy 21.

Emory University School of Medicine – The Down Syndrome Cognition Project

$275,000 RESEARCH CENTER GRANT  AWARDED TO DRS. STEPHANIE SHERMAN (EMORY) AND ROGER REEVES (JOHNS HOPKINS), PRINCIPAL INVESTIGATORS, AND  CO- PRINCIPAL INVESTIGATORS AT FIVE ADDITIONAL INSTITUTIONS:  KENNEDY KRIEGER INSTITUTE, UNIVERSITY OF ARIZONA, UNIVERSITY OF PITTSBURGH, CHILDREN’S NATIONAL MEDICAL CENTER WASHINGTON DC, WAISMAN CENTER/UNIVERSITY OF WISCONSIN.

The consequence of trisomy 21 is a variable constellation of clinically significant outcomes, together called Down syndrome (DS). The cause of the high degree of variability in the presentation (i.e., age of onset and severity) is unknown. Cognitive and behavioral abilities and their variability significantly affect an individual’s quality of life in many ways. Genetic pathways on the background of an extra chromosome 21 are hypothesized to be perturbed and that variation in the genome plays a role in the variable cognitive and behavioral profile. It is also hypothesized that co-occurring medical conditions may affect an individual’s cognitive functioning and behavior. Once these risk factors are identified and the associated altered pathways characterized, it will be possible to find targets for therapeutic intervention. Moreover, the characterization of the variation will form the basis for precision medicine, an approach that provides the clinician with new tools, knowledge, and therapies to select treatments that will work best for an individual. To reach these goals, a clinical and research network has been established through the DS Cognition Project (DSCP). To date, 186 families have completed the entire previously established study protocol with 39 families in progress. This network will be used to complete the first aim, to recruit and assess 60+ new individuals with DS and their families using a revised cognitive and behavioral test battery, implementing a new two-tiered approach to ensure capture of a wider range of abilities. Information from medical records, supplemented by parent interview enables addressing the second specific aim to identify co-occurring conditions and risk factors that modify the presence and severity of DS-associated cognitive phenotypes. Data for this aim will be supplemented by those from collaborators in the London Down Syndrome Consortium (LonDownS). The established BioRepository stores biological samples from individuals with DS and their parents. These samples will be used for the third aim to identify genetic factors that explain the variation in cognition as a basis for therapeutic development. This aim will be expanded by creating a genotype/phenotype database that will form the resource for the large-scale international DS360 project. The current data on participants who have completed at least the Arizona Cognitive Test Battery provide the foundation and strategy for the new components of each aim. The new resources developed in this proposed research, are expected to accelerate the ability to identify possible therapeutic interventions based on the identified biological pathways perturbed by an extra chromosome 21.

University of California San Diego School of Medicine – Defining Genes, Mechanisms and Treatments for Neurodevelopmental and Neurodegenerative Causes of Cognitive Dysfunction in Down Syndrome

$325,000 RESEARCH CENTER GRANT AWARDED TO DR. WILLIAM MOBLEY, PRINCIPAL INVESTIGATOR AND CO- PRINCIPAL INVESTIGATOR DRS. WAGNER, AND WU.

The previous research has documented an important role for the extra copy of the gene for APP (amyloid precursor protein) in the Alzheimer-like neurodegeneration in mouse models of DS. The results show an APP gene dose-dependent degeneration of entorhinal cortex, locus coeruleus (LCN) and basal forebrain cholinergic neurons (BFCN) in a Ds mouse model (Dp16). The widespread presence of p-tau, pre-tangles in these mice was also documented. The findings are consistent with observations in people with DS and encourage the view that studies in mice to explore the underlying mechanisms and treatments may prove useful for combating Alzheimer’s disease in those with DS. During the past year studies were extended in the Ts65Dn mouse to additional models, documenting changes that are characteristic of DS. An important signature of increased APP gene dose is dysregulation of the endosomal system used to import and traffic signals in nerve cells. Endosomes are abnormal in each of the mouse models of DS that harbor three copies of APP it has been shown that this is APP dose dependent and is due to increased levels of the full length APP protein as well as its products called C99 and to Ab42. It is believed that down-regulation of y-secretase is a key factor in inducing activation of Rab5 activity with resulting endosomal dysfunction. The proposed research will build upon recent progress with the launch of new efforts to explore the mechanisms responsible for APP-linked degeneration in DS and to further evaluate APP-directed treatments, and include: 1) Further investigation of molecular mechanisms underlying endosomal abnormalities and neuronal dysfunction caused by APP and its proteolytic products (C99 and Ab42) focusing on Ab effects on y-secretase activity and definition of molecules that mediate activation of Rab5 to produce changes in endosomal structure and function. The studies will also determine whether or not there are trans-neuronal effects of APP toxicity in DS models by selectively reducing APP gene dose to 2N levels in LCNs or BFCNs. 2) Exploration of treatments to prevent and/or reverse APP gene dose induced abnormalities by extending early findings on effectiveness of y-secretase modulators (GSMs) and APP-specific antisense oligonucleotides (ASOs), including studies in vivo, to demonstrate target engagement, efficacy and safety in DS mouse models. 3) Definition of which other genes contribute to reduced axonal trafficking of neurotrophic signaling from endosomes by utilizing mice segment ally trisomic for subsets of genes shared between mouse chromosomes and HSA21 to test candidate genes. It is anticipated that the proposed research will lead to important new insights into the pathogenesis of AD in DS and development of effective therapies.

University of Arizona – Brain Development, Sleep and Learning in Down Syndrome

$250,000 INNOVATION RESEARCH GRANT WAS AWARDED TO PRINCIPAL INVESTIGATOR DR. JAMIE EDGIN AND CO-PRINCIPAL INVESTIGATORS DRS. NADEL, GOMEZ, AND CLARK.

The Edgin laboratory has been at the forefront of efforts to validate and develop cognitive assessments appropriate for use with individuals with Down syndrome (Ds), including the Arizona Cognitive Test Battery (ACTB), the first-ever evidence-based Ds-specific battery. The lab employs rigorous neuropsychological and physiological measures to isolate and assess the mechanisms that drive learning impairments in Ds. During the past year progress has included 1) continued development and validation of a new memory assessment, the Arizona Memory Assessment for Preschoolers and Special Populations (A-MAP), appropriate for young children with Ds and highlight measures of cognitive performance that are effective across a wide age range; and, 2) expanded research on sleep apnea and sleep disruption in Ds, focusing specifically on mechanisms of sleep physiology that may underlie associations between sleep and learning impairments in this population. The proposed research project will: 1) Continue validation of a new android touch-screen tablet-based battery, A-MAP, that will minimize practice effects, sufficiently efficient to eliminate fatigue effects and be useful for much younger children and aged individuals with Ds to address a critical need for outcomes measurement to support intervention and monitoring in clinical trials; 2) Continue the study of sleep and learning in infants and toddlers with Down syndrome, including the follow-up in a longitudinal study tracking the relation of sleep quality to cognitive outcomes and the completion of a study of sleep-dependent learning. It will be determined whether earlier sleep quality predicts children’s growth in language and their achievement of developmental milestones over time; and, 3) Evaluation of the impact of different word-learning procedures on long-term word retention in individuals with Ds. This technique may provide an alternate language-learning route that is less sensitive to sleep disturbances in this population. Collectively, these inter-related studies will result in an efficient, reliable, and sensitive memory assessment battery with multiple forms for use in clinical trials with Ds and also contribute to pinpointing promising targets for intervention in this population as well as provide a deeper understanding of how to best support learning and cognitive development in those with Ds.

Stanford University – Mechanisms Underlying the Roles of Sleep and Circadian Rhythms in the Learning Disability of Down Syndrome

$200,000 INNOVATION RESEARCH GRANT AWARDED TO DR. H. CRAIG HELLER, PRINCIPAL INVESTIGATOR AND CO-PRINCIPAL INVESTIGATORS DRS. GARNER AND ADORNO.

The overall goal is to understand the underlying causes of intellectual disability associated with Down Syndrome (DS), investigate those causes mechanistically, and based on that knowledge, develop approaches and therapeutics to improve the cognitive abilities of individuals with DS. Previous research revealed that short-term chronic treatment of the DS model mouse Ts65Dn with GABA antagonists resulted in long-term normalization of learning and memory. The research is now investigating how that therapy may be acting through sleep and circadian systems. It has been shown that both sleep and the proper circadian phase are essential for the drug action and that the excess GABA is directly or indirectly coming from the circadian system opening a new avenue for possible therapeutic approaches. Cognitive dysfunction associated with Ds may also result from impairments of neuronal stem cell maintenance that is partially controlled by the Usp16 gene that is triplicated in Ds. It has been shown that normalizing the copy number of that gene restores normal neural stem cell numbers in the brain, normalizes expression of a subset of genes with different expression levels in Ds and improves learning and memory. To build on these results, the proposed research will: 1) Apply in vivo electrophysiological methods to investigate the local field potentials (LFPs) and ripples, known to be involved in learning and memory, in wake- and sleep-states before and after treatment with the GABA antagonist pentylenetetrazole (PTZ); and, 2) Further investigate the role of Usp16 in the neurological deficits in Ds by characterizing the effects of Usp16 in establishing and maintaining a functional hippocampal circuitry. The studies will also evaluate the effect of Usp16 copy normalization on learning and memory and progression of neurodegeneration in a Ds mouse model as well as the role of Usp16 in cerebellar development. Overall, these studies will help to characterize Ds physiology through which learning and memory formation is disrupted, how other abnormalities in neural and peripheral tissues are generated by the aneuploidy of Ds, and contribute to the identification and development of potential new therapeutics.

Palo Alto Veterans Research Institute/VA Palo Alto Health Care System  – Improving Adrenergic Signaling for the Treatment of Cognitive Dysfunction in Down Syndrome

$115,000 INNOVATION RESEARCH PILOT GRANT WAS AWARDED TO PRINCIPAL INVESTIGATOR DR. AHMAD SALEHI.

Down syndrome (DS) is the primary genetic cause of learning disabilities in humans. Very similar to Ds and Alzheimer’s disease (AD), the Ts65Dn mouse model of Ds shows significant degeneration of the locus coeruleus (LC) norepinephrine-ergic (NE) system, which has been linked to failure in contextual learning in these mice. Importantly, the research has shown increasing brain NE levels can restore cognitive function Ds mouse models. There has also been a renewed attention on the role of NE-ergic system in cognitive dysfunction in AD. As a strategy to potentially expedite the process of drug development for cognitive dysfunction in Ds, the lab’s research has focused on drugs already in the market acting on the NE – ergic system. It has been found that two drugs, i.e. L-DOPS (an NE pro -drug) and formoterol (a long-acting b2 adrenergic receptor agonist), FDA-approved for other indications, can significantly improve contextual learning in Ts65Dn mice. Additional new studies suggest a bi-directional relationship between NE-ergic system and trophic factor signaling. For example, physical activity has been shown to lead to a significant increase in trophic factors including brain-derived neurotrophic factor (BDNF). The proposed research will continue to: 1) Test whether combining physical exercise with b2 adrenergic agonists in Ds mouse models could induce stronger positive effects on cognitive function than each treatment individually. 2) Continue testing whether quantification of NE metabolites, e.g., 3-methoxy-4-hydroxyphenylglycol (MHPG), in urine and plasma could be used as a biomarker for cognitive function and the assessment of therapy in Ds. 3) Investigate whether exercise-induced increases in PGC-1a serves as mechanistic basis for increased BDNF which can act in synergy with lower doses of b2 adrenergic agonists to improve cognitive function in Ds mousse models. It is expected that this project will advance research and development of potential NE- based therapies for cognitive disabilities in Ds, including aspects related to Alzheimer’s disease.

AC Immune/University of California San Diego School of Medicine  – Phase IB Multi-Center, Double-Blind, Randomized, Placebo-Controlled Dose Escalation Study of the Safety, Tolerability and Immunogenicity of ACI-24 in Adults with Down Syndrome.

$200,000 translational INNOVATION RESEARCH GRANT WAS AWARDED TO PRINCIPAL INVESTIGATORS DRS. A. PFEIFFER AND W. BARTH, AC IMMUNE, and DR. M. RAFII, UCSD/Alzheimer’s disease cooperative study (aDCs) & ADCS Consortium.

AC Immune SA is a Swiss-based (Lausanne) biopharmaceutical company primarily focused on Alzheimer´s Disease drug development.  AC Immune has been developing innovative therapeutics with potential against Alzheimer´s Disease and other conformational diseases along three axes: vaccines, antibodies and small molecules. AC Immune has been developing ACI-24, an anti-Ab-specific vaccine, which is designed to act as an active vaccine stimulating the patient’s immune system to produce beta-sheet conformation-specific antibodies that prevent plaque deposition or enhance clearance of plaques. During preclinical development, ACI-24 has shown high efficacy in vivo in AD animal models by memory restoration and plaque reduction. The vaccine is also characterized by a very high specificity due to generating a conformation-specific antibody response with a favorable safety profile of ACI-24, including the absence of local inflammation in relevant models and T-cell independent mechanism. ACI-24 previously entered an ongoing combined Phase I/IIa clinical trial for mild-to-moderate AD in Scandinavia. Supporting research with a mouse model of DS has demonstrated that the mouse equivalent of ACI-24 induced significant anti-Ab antibody response, decreased Ab in the brain, and improved cognitive/memory function with no detectable astroglial or microglial inflammatory reaction. With the award of the 2015-16 LuMind RDS research grant in January 2016 together with a NIH grant award and AC Immune funding establishing a first-ever private-public partnership for a clinical trial in Ds, AC Immune has initiated an ACI-24 Phase 1b clinical trial study in adults 35 to 45 years of age with Ds. The clinical trial is being conducted in the United States and expected to include 5 trial study sites. The primary objectives of the clinical phase Ib study in Ds are to determine the safety and tolerability of ACI-24 and the induction of an anti-Aβ antibody response. Cognitive function testing and additional biological effects represent secondary outcome parameters. It is anticipated this Phase 1b trial will be completed Q1 2019. Importantly, this represents the first clinical trial to evaluate an anti-Ab (amyloid Abeta derived from APP) therapeutic agent in individuals with Ds.