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Advances in Measuring Therapeutic Efficacy: Optimizing Translational Outcome Measures in Genetic Models of Neurodevelopmental Disorders


Neurodevelopmental disorders (NDDs) are a broad range of conditions characterized by abnormal development of the nervous system during “critical periods” of brain growth and neuronal migration leading to lifelong impairments that are severe and often debilitating. The clinical presentation of NDDs includes a wide range of complex symptoms such as intellectual disabilities, developmental delay, recurring, uncontrollable seizures, lack of communication, poor gross and fine motor abilities, and autism spectrum disorder. There are no cures nor corrective therapies currently available and traditional medicines for symptom alleviation are minimal. To understand the intricacies of the neurobiology underlying a variety of NDDs with similar phenotypes, and potentially identify overlapping common mechanisms, while simultaneously addressing the grand unmet clinical need of efficacious therapeutics, we used and, in some cases, generated, novel preclinical genetic mouse models to identify disease-relevant translational outcome measures. Mouse models provide a valuable system to closely investigate symptoms analogous to human disease phenotypes. With the growing knowledge in genetics, NDD-relevant mouse models (knockout, knockin, humanized, etc.) with high construct validity have been generated to study the causal role of specific genes and how the loss of function contributes to NDD etiology and symptom manifestation. The research herein investigates mouse models of four distinct genetic NDDs and defines robust phenotypes that can be employed to evaluate novel therapeutic approaches. Chapter 1 investigates a novel mouse model harboring a deletion of the regulatory region 1b of the Scn1a gene which encodes for Nav1.1 sodium channel. Haploinsufficiency of SCN1A is associated with epilepsy, including Dravet Syndrome. We discovered that both heterozygous and homozygous deletion of the regulatory element led to behavioral and seizure deficits as well as electroencephalogram phenotypes, such as elevated spontaneous spiking events and spike trains, indicating that the 1b deletion model provides strong evidence to investigate the epilepsy risk gene Scn1a and highlights the importance of functional studies following modulation of regulatory elements in haploinsufficiency-related disorders. Chapter 2 focuses on CDKL5 Deficiency Disorder (CDD), a rare X-linked NDD caused by the deficiency of the gene CDKL5 (cyclin-dependent kinase-like 5), which is essential for normal brain development. Previous studies focused on male subjects from two unique mouse models to avoid any potential confounds of variable CDKL5 expression that results from X chromosome mosaicism in females; however, about 90% of individuals living with CDD are females. We performed comprehensive characterization in both sexes of the two mouse models to reproduce earlier studies in males and extend to the translationally relevant population, females. We discovered clinically relevant phenotypes including hyperactivity, learning and memory deficits, and susceptibility to seizures and abnormal EEG that will allow investigators to advance preclinical testing of therapeutics candidates for CDD in females. Chapter 3 expands on the characterization of the Snord116 deletion model of the NDD Prader-Willi Syndrome, which is caused by a loss of paternal genes on chromosome 15q11-q13a. SNORD116 is a paternally expressed imprinted gene cluster that encodes multiple copies of small nucleolar RNA. We focused on an understudied and key behavioral domain of cognition, using a heterozygous deletion of Snord116 and identified learning and memory impairments, highlighting a broader role of SNORD116, beyond the numerous previous reports focused hyperphagic and metabolic phenotypes. Finally, chapter 4 utilizes the rigorous methodologies we implemented in the earlier chapters spanning a range of behavioral domains, seizures, and electroencephalographic outcome measures to investigate a novel cell-based gene therapy for Angelman Syndrome (AS). AS is caused by the deficiency of the gene UBE3A (ubiquitin protein ligase E3A). To evaluate in vivo efficacy of our approach, we generated an immunodeficient AS mouse model capable of accepting human hematopoietic stem cells for engraftment and multilineage hematopoiesis. Upon delivery of functional UBE3A via transplantation and engraftment of CD34+ cells transduced with a Ube3a lentivector, we demonstrated rescue of AS deficits in the immunodeficient AS mouse model across two developmental time points. Currently, this study is in IND-enabling studies after a thorough review of the pre-IND package submitted to the FDA. Taken together, this research advances our understanding of NDDs and highlights the importance of neurodevelopmental behavior research in identifying clinically relevant phenotypes to meet the ultimate goal of therapeutic rescue.

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