Advances and future directions for tuberous sclerosis complex research

Mustafa Sahin, Elizabeth P. Henske, Brendan D. Manning, Kevin C. Ess, John J. Bissler, Eric Klann, David J. Kwiatkowski, Steven L. Roberds, Alcino Silva, Coryse St. Hillaire-Clarke, Lisa R. Young, Mark Zervas and Laura A. Mamounas.  Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations from the 2015 Strategic Planning Conference.  Pediatric Neurology in press. 

Abstract

On March 10-12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland to assess progress and new opportunities for research in tuberous sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis ( http://www.ninds.nih.gov.ezp2.lib.umn.edu/about_ninds/plans/tscler_research_plan.htm) . In addition to the National Institute of Neurological Disorders and Stroke and Tuberous Sclerosis Alliance, participants in the strategic planning effort and workshop included representatives from six other Institutes of the National Institutes of Health, the Department of Defense Tuberous Sclerosis Complex Research Program and a broad cross-section of basic scientists and clinicians with expertise in tuberous sclerosis complex along with representatives from the pharmaceutical industry. This review summarizes outcomes from the extensive pre-meeting deliberations and final workshop recommendations, and includes: 1) progress in the field since publication of the initial 2003 research plan for tuberous sclerosis complex; 2) the key gaps, needs and challenges that hinder progress in tuberous sclerosis complex research; and 3) a new set of research priorities along with specific recommendations for addressing the major challenges in each priority area. The new research plan is organized around both short-term and long-term goals with the expectation that progress toward specific objectives can be achieved within a five- to ten-year timeframe.

From the article

Clinically, a seminal outcome from this body of work was the recognition that loss of TSC1/2 function causes mTORC1 to become constitutively active in TSC and insensitive to most growth suppressive signals. This discovery led to preclinical and then clinical trials with allosteric mTOR inhibitors, such as rapamycin (sirolimus) and its analogs (often referred to as rapalogs), for the treatment of TSC manifestations (discussed below). More recently, novel mechanistic insights in TSC complex function and mTORC1 signaling are fueling new translational directions beyond the rapalogs. For example, novel anabolic functions induced by mTORC1 signaling have been discovered, including de novo lipid and nucleotide synthesis, which combined with its established role in induction of protein synthesis, underlie its growth-promoting capacity (e.g.,  15 16 17  ). Disrupting the function of the TSC complex also affects feedback and crosstalk mechanisms within oncogenic signaling networks  18 19 20  and activates a variety of adaptive response pathways that enable TSC mutant cells to survive the metabolic stress that stems from uncontrolled mTORC1 signaling (e.g.,  21 22 23 24  ). New therapeutic interventions that selectively destroy cells with chronically activated mTORC1 signaling have been suggested by such studies with the hope of eliminating tumors such as renal angiomyolipomas (AML) and subependymal giant cell astrocytomas (SEGAs) in TSC patients. Preclinical and clinical studies are underway to test such approaches…

Remarkable progress in both clinical and translational research has resulted in FDA-approved agents for the treatment of AML, SEGAs and lymphangioleiomyomatosis (LAM). These efforts have created optimism about the future for additional targeted therapeutic strategies for the tumors that arise in TSC. However, despite these advances, there are still key gaps and questions in TSC pathogenesis, and a need to understand better the underlying disease mechanisms, particularly involving the neurological manifestations of TSC, to catalyze development of novel therapeutic approaches.

In the last four years, the first three randomized placebo controlled double-blind studies in TSC and LAM were published and have changed clinical practice. For LAM, the Multicenter International Efficacy of Sirolimus (MILES) trial randomized 89 women with sporadic or TSC-associated LAM to receive either sirolimus (rapamycin) or placebo for one year, followed by one year of observation . Sirolimus stabilized and, by some measures, improved lung function, while lung function in the placebo arm continued to decline.

For SEGAs, the EXIST-1 trial randomized 117 individuals with TSC to either everolimus or placebo : 35% of patients in the everolimus group had at least 50% reduction in the volume of SEGAs versus none in the placebo group (p<0.0001). For AML, the EXIST-2 trial randomized 118 individuals with AML to everolimus or placebo  27  : 42% of patients in the everolimus group had at least 50% reduction in the volume of AML versus 0% in the placebo group (p<0.0001).

During this period of clinical progress, novel phenotypes and pathogenic mechanisms of TSC continue to be uncovered. These include the increasing recognition of specific subtypes of renal cell carcinoma in children and adults with TSC, the discovery that 80% of women with TSC have evidence of cystic lung disease by age 40, and the identification of “second hits” indicating that sun exposure is likely to be a major factor responsible for the development of facial angiofibromas…

For very young children with TSC, a common seizure type is infantile spasms. Indeed, any child presenting with infantile spasms should have a thorough evaluation for TSC. Vigabatrin is generally accepted as the first line of medical treatment for infantile spasms in children with TSC although it is not yet clear why this drug is so effective in TSC. The lack of an authentic TSC mouse model with infantile spasms is a major limitation in this area of research. .

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A previous non-randomized trial suggested that vigabatrin treatment of TSC infants who developed abnormal electroencephalograms (EEGs) prior to epilepsy onset could prevent seizure development and improve intellectual outcome.  A recent prospective study has identified abnormal EEG as a predictive biomarker of impending clinical seizures in infants with TSC . These studies raise the possibility of seizure prevention in TSC infants if a therapeutic window can be defined and preventive treatment given without toxicity. A randomized clinical trial of early intervention with vigabatrin to prevent seizure development in TSC (EPISTOP) is currently ongoing in Europe, and an NINDS-funded trial to prevent epilepsy and improve neurocognitive outcomes in infants with TSC (PREVeNT) is being launched in the U.S.