Individuals affected with neurodevelopmental disorders (NDDs) exhibit mild to severe intellectual disabilities and may express maladaptive behaviors consistent with attention deficit hyperactivity disorder, obsessive-compulsive disorder, and autism spectrum disorders. Improved medical care, integrated educational opportunities, and symptomatic drug treatment have significantly increased the lifespan and improved daily living skills for individuals with NDDs. Drug therapies designed to address the disease state have been less successful. However, recent translational research in animal models for a number of NDDs show great promise for pharmacotherapy that targets pathology and cognitive deficits specific to these disorders.
The creation and characterization of animal models of NDDs have grown in the last decade, driving a number of promising translational research programs. Manipulating gene expression through transgenic, knockout, and knockin approaches in mice, flies, and worms permits study of the underlying anatomy, pathology, and physiology of disease. Mechanistic insights support the development of drug therapies to mitigate cognitive and behavioral deficits that could be life-changing. For example, pharmacotherapy that improves a child’s capacity to learn should provide nonlinear improvements in cognitive abilities, social function, and independence. Despite recent progress, successful therapies for NDDs require significant additional basic and clinical research.
NDDs can be distinguished by genetic and environmental causes, the nature and site of dysfunction, and the time course of cognitive and behavioral deficits during development. In this review, we focus on NDDs with a known genetic basis. These disorders are easier to characterize with animal models, better defined in terms of mechanism, and most promising for the development of principled therapeutic targets. We will also restrict our discussion to NDDs for which abnormalities in the CNS are localized to individual cells, local circuits of neurons, or specific brain regions. Translational research in animal models has been fruitful for disorders that fit this profile such as Down syndrome, fragile X syndrome, Rett syndrome, neurofibromatosis type 1, tuberous sclerosis, and autism.
The extent of genetic insults and brain pathology underlying NDDs determine the potential for pharmacotherapy. For example, phenylketonuria is a disorder with straightforward genetics and dysfunction in a specific, well-understood molecular pathway 1
. Early intervention with dietary modification reduces or eliminates intellectual disability. Similar improvements in cognitive function are unlikely for other NDDs associated with severely underdeveloped brain regions or abnormal long-range projections such as fetal alcohol syndrome, microcephaly, and lissencephaly 2
. However, some improvements in cognitive function may be possible by addressing dysfunction in even severely malformed regions 3
. The prognosis of pharmacotherapy is better for NDDs caused by subtler changes that affect the function of local neural circuits. Translational research has identified pharmacological interventions that restore inhibitory-excitatory balance in neural circuits, compensate for dysfunctional molecular pathways, or address abnormal neurophysiology or synaptic plasticity. Therapies that address dysfunction in long-term plasticity, including both synapse strengthening via long-term potentiation (LTP) and weakening by long-term depression (LTD), are significant. These processes are generally recognized as the key substrate of learning and memory 4
. Individuals with different NDDs exhibit overlapping sets of deficits due to dysfunction in common brain regions. Pharmacotherapeutic strategies that address shared forms of dysfunction have the potential to mitigate symptoms in different NDDs.
Advances in translational research offer hope to both children and adults. Remarkably, recent findings have shown improvements in learning and memory in adult animals 5,6
. Mutations, deletions, or duplications of genes in NDDs may cause only modest changes in protein expression that shift the equilibrium of chemical reactions and signaling pathways. Thus, therapies that normalize function by either enhancing the activity of remaining proteins, disrupting mutant proteins, or modulating parallel and convergent pathways may improve abilities in individuals with NDDs.
The Translational Cycle
A primary goal of translational research in the field of neurodevelopmental disorders is to replace symptomatic and supportive drug therapies with pharmacotherapies based on a principled understanding of the causes of dysfunction. We define a model of this process as the Translational Cycle. Translational research starts with diagnostic, behavioral and genetic studies in man, moves to animal models and other reduced preparations for biological and neuroscientific study then progresses to drug development and clinical studies in man based on increased knowledge and therapeutic strategies.
We describe this Translational Cycle with seven multidisciplinary steps():
The Translational Cycle describes key events in the development of drug therapies for neurodevelopmental disorders (NDDs)
- Human phenotype – Characterization of the disease
- Human genotype – Discovery of the underlying genetics
- Animal genotype – Development of animal models that mimic the genetic etiology of human disease
- Animal phenotype – Behavioral testing to probe cognitive, motor, and social behaviors; studies of underlying genetics, molecular biology, neurophysiology, and anatomy in animal models
- Therapeutic strategy – Development of therapeutic strategies based on biological findings in animal models and optimization for safety and efficacy
- Drug development – Optimization of lead compounds to improve drug-target specificity, bioavailability, or pharmacokinetics, as well as determination of appropriate dose, dosing strategy, and route of administration.
- Clinical trials – Design and execution of clinical trials in man to address cognitive deficits
In the first step of the Translational Cycle, human disorders are identified as distinct from each other and the phenotypes are characterized (, step 1). The first NDDs described in this manner were common disorders with external traits including skin lesions and benign tumors in neurocutaneous syndromes such as tuberous sclerosis 7–9
and craniofacial abnormalities in Down syndrome 10
. Today, NDD diagnosis relies on detailed genetic and cognitive testing, behavioral phenotyping and, in some cases, neuroimaging. Improved characterization of NDDs to identify relative cognitive strengths and weaknesses (, step 1) has focused animal behavioral studies and determined brain regions of interest. For instance, human deficits in executive control and long-term memory implicate the frontal cortex and hippocampus, respectively.
Description of genetic causes of NDDs is a necessary step to enable the study of disease in animal models (, step 2). Down syndrome was the first disorder described on the basis of genetics due to the triplication of some or all of chromosome 21 11
. Due to a revolution in human genetics, the genes, alleles, expression patterns, epigenetic factors, and patterns of inheritance that underlie various NDDs have been described.
Animal models form the foundation for detailed studies of the biology responsible for cognitive dysfunction in various NDDs (, step 3). Tools for genetically modifying mice and flies include addition or removal of genes, inducible expression of genes at particular developmental time points, and specificity of expression in cell types or tissues 12
. Studies in animal models reveal mechanisms of dysfunction and suggest therapies that target these pathways and systems. However, the value of transgenic animal models is limited by the correspondence of molecular, anatomical, physiological, and behavioral pathology in animals to that in man. Careful study of brain pathology and mouse behavior establishes how well an animal model represents human disease (, step 4). Therapeutic strategies are evaluated in animal models by measuring markers of dysfunction and performance in behavioral tasks (, step 5). A particular therapeutic strategy may address only a subset of cognitive functions, so multiple therapeutic strategies that target distinct deficits and brain areas are desirable.
Significant efforts are required to translate a viable therapeutic strategy into an approved drug. Drug development optimizes a therapeutic compound to improve drug-target specificity, reduce or eliminate dangerous side effects, and determine dose and route of administration (, step 6). Next, a lead compound enters clinical trials in man to test safety and efficacy of therapeutic strategies discovered in animal models (, step7). For drugs intended to address intellectual deficits, trial design can be difficult due to relatively insensitive outcome measures such as cognitive tests. Moreover, outcome measures based on caretaker questionnaires are susceptible to bias, and the correspondence of improved outcome measures with higher functioning in daily living skills may not be straightforward. An approved pharmacotherapy for an NDD would reduce one or more cognitive deficits or maladaptive behaviors. Such a therapy completes the Translational Cycle by addressing the disease phenotype.
Important translational research challenges remain despite significant advances in the development of potential therapeutic strategies for NDDs. Animal models are often an imperfect representation of human disease or developmental disorders, and the differences between species may carry special significance for disease pathology. Moreover, higher cognitive functions in man such as language do not exist in mice or flies. Thus, improved characterization of animal models of NDDs requires better behavioral assays and physiological measurements. New animal models may improve the correspondence with human conditions. More specific and efficacious second-generation therapies require improved description of the mechanisms underlying successful pharmacotherapeutic intervention. A second set of challenges concern clinical development (, steps 5–7). Clinical development programs are expensive and low yield. Raising funds through government, philanthropic, and industry sources is challenging and slow.
In the following sections, we review translational research progress for several well-studied genetically-based childhood NDDs with an emphasis on research in animal models.