Mechanistic Target of Rapamycin (mTOR) in Tuberous Sclerosis Complex-Associated Epilepsy

Abstract

Background

Tuberous sclerosis complex is a multiorgan disease resulting from a mutation of one of two TSC genes. The two gene products form a functional complex that regulates the mTOR signaling pathway (mTOR initially represented mammalian target of rapamycin, but increasingly the term mechanistic target of rapamycin is used to reflect the ubiquitous occurrence of mTOR). Epilepsy is the most common neurological symptom of tuberous sclerosis complex, occurring in 80% to 90% of affected individuals over the course of their lifetimes and causing significant morbidity and mortality. The mechanistic target of rapamycin (mTOR) signaling pathway is intricately involved in multiple cellular functions—including protein synthesis, cell growth and proliferation, and synaptic plasticity—which may influence neuronal excitability and precipitate epileptogenesis. Recent preclinical and clinical studies have increased interest in the potential role of mTOR inhibitors for the treatment of tuberous sclerosis complex-related epilepsy.

Methods

Medline and PubMed database searches were used to identify relevant studies and other information on tuberous sclerosis complex-related epilepsies, the mTOR pathway, and current advances in treatment approaches.

Results

Although current management strategies that provide symptomatic relief are effective at reducing the frequency of seizures in individuals with tuberous sclerosis complex, there is further room for the exploration of therapies that directly address hyperactive mTOR signaling—the underlying etiology of the disease. The role of the antiepileptic effect of mTOR inhibition was first demonstrated in knockout TSC1 mouse models. Additionally, several case studies demonstrated a positive effect on seizure frequency and severity in patients with pharmacoresistant epilepsy. In a phase 1/2 clinical trial with 28 patients, clinically relevant reduction in overall seizure frequency was documented in individuals treated with the mTOR inhibitor everolimus. In a phase 3 trial evaluating the role of everolimus in subependymal giant cell astrocytoma, seizures were a secondary end point. Because the median seizure frequency was zero in this study, the analysis was inconclusive.

Conclusion

Various preclinical models provide substantial evidence for the role of mTOR inhibition in the treatment of epilepsy in individuals with tuberous sclerosis complex. Preliminary clinical studies provide supportive evidence for a role of mTOR inhibition in the management of tuberous sclerosis complex-associated epilepsy and pave the way for new randomized placebo-controlled studies. This article reviews current treatment recommendations for the management of tuberous sclerosis complex-associated epilepsy as well as the rationale and evidence to support the use of mTOR inhibitors.

Introduction

Tuberous sclerosis complex (TSC) is a rare, autosomal-dominant genetic disorder with an incidence of approximately 1 in 6000 and a global prevalence of approximately one million people.¹ The hallmark of TSC is the development of benign tumors and lesions in various organs, including the brain, kidneys, lungs, heart, eyes, and skin.² Epilepsy is the most common symptom in patients with TSC and has been reported in up to 96% of patients in hospital-based studies.2, 3 TSC is caused by inactivating mutations in TSC1 or TSC2 tumor suppressor genes.¹ In addition to germ line mutation of TSC1 or TSC2, a somatic second “hit” mutation that causes loss of heterozygosity in the unaffected TSC allele is also required for tumor development.2, 4 TSC1 and TSC2 encode the proteins hamartin and tuberin, respectively.5, 6 Tuberin is a guanosine triphosphate-activating protein that is known to inhibit the rat sarcoma-related superfamily of small G proteins.4, 6 Ras homolog enriched in brain, a member of this superfamily, is the specific guanosine triphosphate downstream of tuberin, and it has been identified as the major regulator of the mechanistic target of rapamycin (mTOR), a master regulator of cell growth, proliferation, and survival.⁷ Hamartin acts as a chaperone for tuberin, preventing it from self-aggregating and maintaining it in a soluble cytosolic complex that blocks mTOR activation by inhibiting ras homolog enriched in brain.⁸ Therefore, when TSC1 or TSC2 are inactivated, such as in individuals with TSC, hamartin or tuberin function is lost, and the mTOR signaling pathway becomes overactivated, leading to unchecked cell growth and proliferation, metabolism, and angiogenesis.2, 9

Dysregulation of mTOR signaling in the brain leads to neuronal abnormalities that can translate into clinical the neurological manifestations in TSC. TSC should now be considered as one of the “mTORopathies,” a group of disorders that includes focal cortical dysplasia and hemimegalencephaly. Common histopathologic characteristics, such as cytomegaly and cortical dyslamination, and a tendency toward early onset and intractable seizures, can be found among these disorders.¹⁰ In addition to epilepsy, other neurological pathologies associated with TSC have a broad spectrum, including neuropsychiatric disorders (intellectual disability, autism spectrum disorders, attention-deficit and hyperactivity disorder, challenging behavior, mood and anxiety disorders, and depressive disorders) and brain lesions (cortical tubers, subependymal nodules, subependymal giant cell astrocytomas [SEGAs], and white-matter abnormalities).2, 4 (Table 1) Cortical tubers and white-matter abnormalities are both cortical dysplasias that have been associated with epilepsy and learning difficulties in people with TSC.11, 12, 13, 14 This review provides an overview of epilepsy in TSC, current treatment recommendations, and the contribution of aberrant mTOR signaling to epileptogenesis in TSC. It also highlights important preclinical and clinical studies that investigate the use of mTOR inhibitors as a novel treatment for TSC-associated epilepsy. The rationale for the use of mTOR inhibitors as a unique pathogenesis-based systemic treatment for TSC-associated epilepsy in light of current treatment options for epilepsy is presented in this review.