Targeted treatment trials for tuberous sclerosis and autism: no longer a dream

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Genetic disorders that present with a high incidence of autism spectrum disorders (ASD) offer tremendous potential both for elucidating the underlying neurobiology of ASD and identifying therapeutic drugs and/or drug targets. As a result, clinical trials for genetic disorders associated with ASD are no longer a hope for the future but rather an exciting reality whose time has come. Tuberous sclerosis complex (TSC) is one such genetic disorder that presents with ASD, epilepsy, and intellectual disability. Cell culture and mouse model experiments have identified the mTOR pathway as a therapeutic target in this disease. This review summarizes the advantages of using TSC as model of ASD and the recent advances in the translational and clinical treatment trials in TSC.

Highlights

► Mouse models suggest the possibility of rescue of neurological symptoms in TSC. ► mTOR inhibitors have proven clinically effective in TSC-associated tumors. ► mTOR inhibitors are currently being tested for efficacy in neurocognitive outcomes in children with TSC. ► Investigating TSC and other genetic disorders associated with ASD may lead to the development of therapies for neurodevelopmental disorders.

Introduction

Autism spectrum disorders (ASD) affect approximately 1% of children in the United States, and are characterized by defects in social interaction, language delay, and repetitive interests or behaviors. ASD is a major public health problem that disrupts families and leads to significant disability, resulting in a total annual societal cost of ∼$35 billion to care for and treat autistic individuals [1]. When initially described by Kanner in the 1940s, researchers believed that this disorder of behavior and cognition resulted from emotional deprivation in infancy [2]. This notion has long since been discarded, and rather it has been recognized that neuronal dysfunction occurs in early brain development in individuals affected with ASD [3, 4, 5]. In the last decade or so, we have started to undertake the studies needed to understand the underlying etiology of ASD. Genes play a greater role in the risk of ASD than in any other common neurodevelopmental disorder, with estimates of heritability as high as 60–90% [6•, 7•]. However, the genetic cause is unknown in most cases. Collectively, rare copy number variants (CNVs) account for the largest category (6–8%) of known genetic causes of ASD. Combining recurrent CNVs and single gene Mendelian disorders, known genetic causes currently account for less than 15% of ASD cases [8•, 9]. Since each of the rare CNVs associated with autism is identified in a very small number of individuals with ASD, leads to alterations in dosage of a relatively large number of genes, and demonstrates phenotypic variability of expression, it is not yet clear how we will be able to utilize this knowledge to develop therapeutics. Identifying the key gene(s) in CNVs is likely to take some time. In contrast, single-gene disorders associated with ASD appear to provide us with a critical opportunity to understand and develop treatments for ASD since they provide both a much larger number and more homogenous group of patients to study. Thus, ASD studies that leverage findings from these single-gene disorders have the potential to elucidate both the underlying neurobiology of ASD and to identify therapeutic drugs and/or drug targets.

Until recently, Mendelian etiologies with high penetrance of ASD such as fragile X syndrome, tuberous sclerosis complex (TSC), and Rett syndrome had been relatively ignored in autism research. For several decades, most of the research in the ASD field was focused on ‘pure’ or ‘idiopathic’ autism. In fact, much of the imaging and cognitive neuroscience studies were performed on a relatively small segment of the ASD population with ‘high functioning autism’ and without known genetic syndromes. This was an unusual approach in neuroscience since research on diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis have benefited enormously from the study of familial cases with known genetic causes. However, ASD researchers have recently turned to the opportunities provided by the Mendelian disorders strongly associated with autism. A case in point is TSC. This review summarizes the recent progress in TSC translational and clinical research, as an example of how a Mendelian disorder can be used to investigate early detection and development of effective treatments for ASD.

Section snippets

The case for tuberous sclerosis complex in ASD research

TSC is a multisystem genetic disorder in which 90–95% of the affected individuals have CNS involvement. Epilepsy occurs in 80–90% of these patients and can be medically refractory [10, 11]. Approximately 45% of TSC patients have mild-to-profound intellectual disability, and ASD occurs in up to 50% of TSC individuals [10, 12]. The neuropathological findings in the TSC brain typically include subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs) and cortical tubers [13].

Basic cell biology of TSC in neurons

Studies performed both in vitro and in vivo using mouse models have demonstrated that the Tsc1 and Tsc2 proteins play crucial roles not only in cell growth, but also in axonal, dendritic and synaptic development and function. On the axonal side, TSC1/2 proteins regulate axon specification, guidance, myelination and regeneration. In cultured hippocampal neurons undergoing early neuronal polarity determination, TSC pathway components are expressed in a polarized manner, much higher in nascent

Mouse models of TSC can be treated with mTOR inhibitors

Several mouse models of TSC have been generated and all of them display neurocognitive deficits [24, 28, 35, 36, 37], many of which can be reversed with treatment with mTOR inhibitors [28, 35]. For example, Tsc1+/− mice show impaired learning in hippocampal-dependent learning tasks and impaired social behavior, supporting a model in which haploinsufficiency for the TSC genes leads to aberrations in neuronal functioning resulting in impaired learning and social behavior [36]. Similarly, Tsc2+/−

Human clinical trials with mTOR inhibitors in TSC

In parallel with the basic neurobiology research in the role of TSC1/2 in brain development, there has been major progress in the use of mTOR inhibitors in several aspects of medical care (Figure 1). Following the discovery of rapamycin in the 1970s, rapamycin and related mTOR inhibitors have been developed for several clinical indications; first to prevent solid organ transplant rejection, and later to prevent stenosis of artificial coronary stents and treatment for several types of cancer.

Need for biomarkers

An abundance of clinical and basic science evidence suggests that mTOR inhibitors represent a rational candidate for the treatment of neurodevelopmental disabilities in TSC. However, mTOR inhibitors can have side effects, such as immuno-suppression and endocrine dysfunction. Given the prominent role of the mTOR pathway in many normal physiological functions, there is also the theoretical risk of adverse effects on growth and development, especially early in life. Despite these risks, steps can

Conclusions: other barriers and future directions

While the excitement over our ability to finally offer mechanism-based treatment options for rare genetic diseases is warranted, we should recognize that there are still several obstacles to performing treatment trials in neurodevelopmental disorders. One obvious difficulty is the risk–benefit analysis. For many parents whose children are affected with ASD and other neurodevelopmental disorders, treatment trials offer the hope of their child having more effective communication or enhanced

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I am grateful to Kira Dies for assistance with the figure/table and Drs. Elizabeth Berry-Kravis, Sarah Spence, David Kwiatkowski and Steven Roberds for critical reading of the manuscript. I would like to thank all members of the TSC communities for many helpful discussions. Owing to limited space I have not quoted all the literature in this field, and I apologize to those whose articles are not referenced. The clinical trial (NCT01289912; PIs Sahin, Franz, De Vries) is funded by Novartis,

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      Given the fact that mTOR signaling pathways affect an array of cellular functions, including cell cycle kinetics, cellular differentiation, cell growth, cell survival, metabolism and protein synthesis, it is not surprising that genetic variations of genes coding for upstream regulators and downstream effectors of mTORC1 have been associated with ASDs (Crino, 2011; Hoeffer and Klann, 2010). Consistent with the pathogenic role of mTORC1 overactivity, several proof of concept/proof of principle studies showed that treatment with rapamycin attenuated severity of behavioral and neuropathological findings in transgenic mouse models of TSC (Meikle et al., 2008; Sahin, 2012; Talos et al., 2012; Tsai et al., 2012). Additionally, there are data from relevant mouse models of TSC to suggest that addressing the metabolic lesion (i.e., disinhibited mTOR signaling activity) may have beneficial effects on behavior in “adolescent” mice (Ehninger, 2013; Talos et al., 2012).

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