UNLOCKING A CURE FOR TUBEROUS SCLEROSIS COMPLEX. An Assessment of Scientific Progress and Research Needs

Transcription

1 UNLOCKING A CURE FOR TUBEROUS SCLEROSIS COMPLEX An Assessment of Scientific Progress and Research Needs A White Paper by: Vicky Holets Whittemore, PhD 801 Roeder Road, Suite 750 Silver Spring, MD

2 ABSTRACT Significant progress has been made in tuberous sclerosis complex (TSC) research and clinical care following cloning of the TSC1 and TSC2 genes and identifying their role in the mammalian target of rapamycin (mtor) signaling pathway. The goal of this study was to identify areas of highest research need in TSC. A survey of basic, translational and clinical research key opinion leaders (KOLs) was conducted to identify the significant progress that has been made, the areas of TSC research where less progress has been demonstrated, unmet medical needs of individuals with TSC, and future research and clinical needs, as well as barriers to progress. A telephone survey was conducted with twenty-seven KOLs, and the results were collated into a summary of the findings which was reviewed by the KOLs. Comments and clarifications were incorporated into the final results. The results highlighted research that moved the understanding of the underlying mechanism(s) of TSC forward in a significant way and that resulted in improvement in the clinical care and quality of life for individuals with TSC. The results also highlighted areas where more research is needed. The most significant progress in TSC was identifying and characterizing the role of the TSC1 and TSC2 genes in the mtor signaling pathway. Increased focus on research on the central nervous system manifestations of TSC and clinical care for adults with TSC is warranted. INTRODUCTION Tuberous sclerosis complex (TSC) is a genetic disorder with an estimated incidence of one in 6,000 live births 1. TSC is a multisystem disorder that may affect one or several organ systems, with variable penetrance even within the same family. Two genes, the TSC1 gene on chromosome 9 2 and the TSC2 gene on chromosome 16 3 have been identified. More than 2/3 of the cases are reported to be spontaneous mutations (de novo mutations), with only 1/3 of the cases being familial. The first detailed description of the central nervous system symptoms and pathology of TSC was provided by Bourneville, who used the term tuberous sclerosis of the cerebral convolutions to describe a child with seizures and learning disability 4. Over the years, the diagnosis of TSC has undergone significant changes as more was learned about the disease, the genes were identified allowing for molecular diagnostic testing, and the variability of the manifestations of the disease was appreciated 5,6. Initially, the diagnosis was based on the Vogt triad of mental retardation, facial angiofibromas (incorrectly called adenoma sebaceum), and seizures 7. Manuel Gomez, MD was the first to recognize and document the full extent of the manifestations of disease and established the first diagnostic criteria that based the diagnosis on identifying the presence of major and minor manifestations that together would lead to a definite, probable or possible diagnosis 8. These diagnostic criteria were later revised to reflect new knowledge about the disease 9, and continue to be used for clinical diagnosis of TSC in conjunction with molecular diagnostic testing. While many individuals with TSC will develop a severe neurological phenotype (epilepsy, autism spectrum disorder, cognitive disability), it is now clear that individuals with TSC may have very minor clinical features and only present for diagnosis in adulthood due to medical issues and/or after one of their children is diagnosed with TSC. There are no recent epidemiological studies in the USA that document the true incidence and prevalence of TSC, and the previous studies were completed more than 20 years ago on a small population of individuals with TSC 10.

3 The majority of individuals with TSC will have a normal life expectancy. However, medically refractory epilepsy, polycystic kidney disease, renal angiomyolipoma with life-threatening hemorrhage, renal cell carcinoma, cardiac failure due to cardiac rhabdomyomas, and progressive lymphangioleiomyomatosis (LAM) may impact an individual s life expectancy 10. In addition, the presence of learning disabilities, psychiatric diagnoses, including anxiety disorders, depression, and autism spectrum disorder, may severely impact an individual s quality of life 11,12,13. TSC can affect almost every organ system with significant variability between individuals with TSC. There is a high incidence of many significant clinical problems in individuals with TSC overall, including epilepsy, autism spectrum disorder, anxiety disorder, benign tumor growth and LAM 14. Progress in understanding the underlying mechanisms of disease has been greatly assisted by the identification of the TSC1 and TSC2 genes and the ability to perform molecular diagnostic testing. The role of the TSC1/2 gene complex in the mammalian target of rapamycin (mtor) signaling pathway led to the development of numerous animal models of TSC that are now utilized in research studies. Having gone from gene cloning to understanding the role of the genes to clinical trials in a short period of time has placed TSC in the role of a model system for studying and better understanding a rare genetic disorder 14,15. Understanding the factors that lead to tumor growth, epilepsy or autism spectrum disorder in individuals with TSC may lead to a better understanding of the underlying mechanism(s) in these disorders in the general population 15. The goal of this survey is to identify the areas of TSC clinical care and research where significant progress has been made, areas where research is needed, the barriers to progress in TSC research, and the unmet clinical needs of individuals with TSC. This survey attempts to identify the key challenges in finding new treatments and a cure for TSC, as well as to discuss issues discussed by key opinion leaders in the TSC community regarding the needs of the research and clinical community in their research efforts and to provide care for individuals with TSC. Recommendations are provided for the critical research areas that need focused attention, support and funding in order to find a cure for TSC while improving the lives of those affected. Identifying these areas will be the first step toward unlocking a cure for TSC, and hopefully for many other disorders. METHODS Twenty seven key opinion leaders (KOLs) were interviewed regarding their views and opinions on the progress in our understanding of the clinical features of TSC, the status of basic and translational science on TSC, areas of unmet needs in both clinical care and research, and barriers and challenges to making progress in these areas. The KOLs are all experts in basic, translational and/or clinical research on TSC, as well as health care providers who have a particular interest and expertise in providing clinical care for individuals with TSC. The KOLs were interviewed by telephone by the author, and all were asked the same questions for the survey during the interview. The questions focused on 1) the major advances in TSC research; 2) the barriers to progress in TSC research and clinical care; and 3) the unmet clinical needs of individuals with TSC. A draft of the survey results were reviewed by all of the KOLs and additional comments and clarifications were incorporated into the final discussion and recommendations. DEFINING A CURE FOR TSC The consensus of the KOLs is that finding a cure for TSC will be a significant challenge due to the genetic nature of the disease and the fact that so many of the individuals with TSC have de novo mutations. Gene therapy is not likely to be a meaningful approach to treating TSC because the most significant manifestations of the disease, those affecting the central nervous system, are in place at birth. However, improvements in diagnosis of TSC leading to earlier diagnosis and recognition of those individuals who are at 2

4 risk for epilepsy, neurodevelopmental and cognitive delays would lead to earlier treatment and therapies that may prevent the impact of the disease. Currently, the goal would be to identify treatments that normalize the lives of individuals with TSC so that they can lead healthy and productive lives. AREAS OF TSC RESEARCH WITH SIGNIFICANT PROGRESS There was very little research on TSC until the TSC1 and TSC2 genes were identified in the 1990s, and the subsequent findings that the protein products of these genes, hamartin and tuberin, respectively, play a critical role in regulating cell growth, cell proliferation and organ size and in the mtor signaling pathway 19,20. The cellular effects of TSC1/2 gene disruption identified in vitro were also shown in some tumors from TSC rodent models and human TSC or LAM lesions 19, These findings, along with preclinical studies that showed a response to treatment with mtor inhibitors 19,22,33 led to the current clinical trials. Most notably, recent studies have shown that treatment of animal models of TSC with mtor inhibitors can not only prevent the onset of seizures 34 and cognitive deficits 35 in young animals, but can also treat seizures 34 and reverse cognitive deficits 35 in older animals. These significant findings indicate that deficits and manifestations of disease due to the underlying molecular mechanism in TSC may be both preventable and in some cases, reversible 36,37. At this time, clinical trials for renal angiomyolipomas (AMLs) 38,39, subependymal giant cell astrocytomas (SEGAs) 40,41, facial angiofibromas, lymphangioleiomyomatosis (sporadic and associated with TSC) 39,42, cognition and epilepsy are either completed or currently underway. Based on the data from a Phase II trial 41, the Food and Drug Administration approved Afinitor, manufactured by Novartis Oncology, for treatment of SEGAs associated with TSC. Phase III trials for treatment of SEGAs and for treatment of renal angiomyolipomas were completed in The results of the completed trials indicate that SEGAs and renal AMLs decrease in size in response to treatment with mtor inhibitors, but that the majority of tumors regrow once the treatment is stopped 38,40. The rapid progress from identification of the genes, to identification of their role in the mtor pathway, to clinical trials has provided specific treatments for individuals with TSC for the first time. Although the clinical trials with mtor inhibitors show reduction in the size of tumors in individuals with TSC, results of the clinical trials show that the tumors regrow once the treatment is stopped. The KOLs agreed that there is significant need to identify new drug targets and potential treatments for TSC that not only reduce the size of the tumors, but cause the tumors to permanently regress. The need for biomarker(s) that can be utilized to study progression of disease as well as response to treatment are needed for TSC and LAM. A recent study shows that blood levels of VEGF-D may be a reliable biomarker for individuals with LAM 43, but it remains to be characterized in a large group of individuals with TSC. Recommendations: Expand preclinical and clinical research to identify new drug targets (such as mtorc1, mtorc2, Rheb, VEGF-D, MAPK, LKB1/AMPK pathway, among others) and potential new compounds and drugs to treat the various manifestations of TSC by testing drugs in combination with, or instead of mtor inhibitors; Identify and characterize biomarkers that measure progress of disease and/or response to treatment in both TSC and LAM; Continue research to understand the role of gene dysfunction that leads to specific manifestations of TSC, specifically cognitive deficits and epilepsy, such that prevention strategies can be identified. 3

5 AREAS IN NEED OF ADDITIONAL RESEARCH Although much is now known about the role of the TSC1/2 complex in the mtor signaling pathway, very little is understood about how disruption of this complex due to a mutation in one of the TSC genes actually results in the specific manifestations in TSC or the timing of their appearance in individuals with TSC. There is also very little known about the significant variability of the disease, even between family members who carry the same mutation in either the TSC1 or TSC2 gene. In addition, there is a significant number of individuals whose mutation can not be identified using modern sequencing techniques for which the suggestion has been made that there may, in fact, be additional genes for TSC that have not been identified. Clearly the most debilitating manifestations of TSC are those that affect the central nervous system. Attempts have been made to correlate the number, location and size of cortical tubers with intellectual impairment and autism spectrum disorder. However, there are individuals with TSC who have a significant tuber load and have normal intelligence while there are others with very little tuber load who have significant intellectual disability and/or autism spectrum disorder. Early onset of seizures that are not well controlled with medication appears to be one of the most significant factors involved in cognitive outcomes, but no large scale studies have documented this correlation. Recommendations: Identify the underlying mechanism(s) involved in the development of specific manifestations of TSC; Focus genetic studies on identification of additional genes for TSC (i.e., TSC3, TSC4, etc.) and/or mutations that are not currently detected using sequencing or other current techniques. Expand research on the potential for genetic modifiers that lead to variability of phenotype between individuals with the same mutation so that there is a clearer path to predict severity of outcome and lead to personalized medical care for each individual with TSC. Gain an understanding of the underlying molecular mechanism(s) that result in epilepsy, autism spectrum disorder, learning disabilities, anxiety and other psychiatric conditions in individuals with TSC, and develop treatments and preventative strategies where possible. Increase basic research on the causes(s) of cognitive and intellectual disabilities using animal models of TSC and perform critical clinical studies of individuals with TSC. UNMET MEDICAL NEEDS OF INDIVIDUALS WITH TSC There is a significant need for early diagnosis and aggressive treatment of TSC in order to optimize outcomes for individuals with the disease. Too many individuals with TSC, especially infants and young children, go for weeks with undiagnosed seizures that if diagnosed early and treated aggressively would likely lead to better outcomes for these children. There was a consensus of the KOLs that new screening tools are needed to diagnose infants with TSC prior to the onset of seizures, whenever possible, and to intervene with effective treatments as quickly as possible when seizures begin. Some KOLs suggested that it may be possible to prevent seizures in infants with TSC by early screening of the EEG and treatment of an abnormal EEG prior to the onset of seizures. Since as many as 40% of infants with TSC develop infantile spasms, identifying methods for early diagnosis and preventative treatment would result in optimal outcomes for these children. 4

6 The KOLs noted that there has been research done that identifies the cognitive and intellectual disabilities in individuals with TSC, but very little research has addressed the potential cause(s) and/or treatments. The first clinical trial to directly address a treatment for the neurocognitive issues in children with TSC began in 2011, but clearly much more basic research utilizing animal models of TSC is needed to gain an understanding of the causes of the cognitive and intellectual disabilities in TSC. The KOLs also agreed that there is a critical need for physicians who treat adults with TSC to have a better understanding of the possible manifestations of the disease, and to treat the whole individual in a comprehensive and multidisciplinary manner. A network of TSC Clinics in the USA provides clinical care to individuals with TSC, with 18 out of the 30 clinics providing care to adults with TSC. However, for many individuals with TSC the transition from pediatric to adult care is not smooth, as for many individuals with rare genetic disorders, and in some areas this care is nonexistent. 5 Recommendations: Develop screening methods that provide early diagnosis of TSC; Identify infants with TSC who are at risk for developing seizures, especially infantile spasms, and develop preventative treatments leading to optimal clinical outcomes; Continue to increase the knowledge of the impact of TSC on adults with the disease and increase the number of centers that provide comprehensive, multidisciplinary care for these individuals. Identify and characterize biomarkers for detecting disease progression and response to treatment. BARRIERS TO PROGRESS IN TSC RESEARCH For many years, the barriers to progress in TSC research were the lack of researchers, clinicians and funding for this rare genetic disease. A small, but very dedicated group of researchers pushed the knowledge about TSC from the identification of the genes, to an understanding of the role of the TSC1/2 complex in the mtor pathway, to the current clinical trials in less than 15 years. In the grand scheme of disease research, this is rapid and remarkable progress. In the lives of individuals with TSC, and for those who have lost their lives to the disease, the progress is not rapid enough. The TS Alliance provided the first research grant award in 1984, and since that time has funded $15.3 million in basic, translational and clinical research. The goal of the TS Alliance has been to fund small seed grants that allowed investigators to develop preliminary data in order to compete for funding from larger organizations and the National Institutes of Health. The TS Alliance has also provided funding for resource development that would assist the TSC community overall annual workshops to bring together the genetic researchers at the American Society of Human Genetics meeting for exchange of information and data; international TSC research conferences in 1998, 2002, , 2009 and 2011; support for the TSC1/2 Variation Database; development and expansion of the TSC Natural History Database that contains clinical data on more than 1,100 individuals with TSC; and animal models of TSC. Support for TSC research funded by NIH has increased significantly since the identification of the genes and the role of the proteins in regulating the mtor in 2002 (see Figure 1). A tremendous boost for TSC research funding has come from the TSC Research Program in the Congressionally Directed Medical Research Program in the Department of Defense. To date, $35.9 million have been provided through this program specifically for TSC research (Figure 1).

7 Please note: TS Alliance funding for FY10 includes 18 months due to a change in fiscal year. Figure 1 However, even with all of these avenues for research funding, funding is incredibly competitive at all levels. The KOLs stated the need for additional research funding at all levels in order to expand current research efforts. Many of the KOLs also noted the significant need for a clinical trial network that would help to facilitate, streamline and support the development and performance of clinical trials. There was also substantial support for increased funding specifically focused on the neurological manifestations of TSC which often have the largest impact on the quality of life for individuals with TSC and their families. Recommendations: Increase funding for TSC research at all levels; Increase support for translational research, including preclinical drug screening and testing of compounds and drugs for use to treat manifestations of TSC; Provide support for a clinical trial network that would increase the number of clinical trials for TSC, as well as increase efficiency and reduce cost to carry out the trials; Continue to support and expand TSC research resources that are utilized by the community (TSC Natural History Database, TSC1/2 Variation Database, sharing of animal models, cell lines, etc.) CONCLUSIONS In conclusion, research on TSC is poised for providing new therapies that modify the progression of the disease, and possibly even prevent some of the most devastating manifestations. It will likely not be possible to unlock a cure for TSC in the near future, but with focused research efforts new treatments will significantly improve the lives of those affected, and will provide clues for treatment of other disorders. Copyright December 2011, Tuberous Sclerosis Alliance. All rights reserved. This White Paper was supported with a generous grant from the Charles and Mildred Schnurmacher Foundation. 6

8 KEY OPINION LEADERS INTERVIEWED FOR WHITE PAPER E. Martina Bebin, MD, MPH; University of Alabama, Birmingham, AL John Bissler, MD; Children s Hospital Medical Center, Cincinnati, OH John Blenis, PhD; Harvard University, Boston, MA Peter Crino, MD, PhD; University of Pennsylvania, Philadelphia, PA Paolo Curatolo, MD; Tor Vergata University Hospital, Rome, Italy Sandra Dabora, MD, PhD; Brigham & Women s Hospital, Boston, MA Orrin Devinsky, MD; New York University, New York, NY Petrus de Vries, MD, PhD; Cambridge University, Cambridge, UK Kevin Ess, MD, PhD; Vanderbilt University, Nashville, TN Jane Fountain, PhD; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD David Franz, MD; Children s Hospital Medical Center, Cincinnati, OH Michael Frost, MD; Minnesota Epilepsy Group, St. Paul, MN Kuan-Li Guan, PhD; University of California, San Diego, CA Elizabeth Petri Henske, MD; Brigham & Women s Hospital, Boston, MA Sergiusz Jozwiak, MD, PhD; The Children s Memorial Health Institute, Warsaw, Poland David Kwiatkowski, MD, PhD; Brigham & Women s Hospital, Boston, MA Brendan Manning, PhD; Harvard University School of Public Health, Boston, MA Hope Northrup, MD; University of Texas Health Science Center, Houston, TX Mustafa Sahin, MD, PhD; Children s Hospital/Harvard University, Boston, MA Julian Sampson, MB; Cardiff University, Cardiff, UK Alcino Silva, PhD; University of California, Los Angeles, CA Elizabeth Thiele, MD, PhD; Massachusetts General Hospital, Boston, MA Cheryl Walker, PhD; University of Texas MD Anderson, Smithville, TX Howard Weiner, MD; New York University, New York, NY Michael Wong, MD, PhD; Washington University, St. Louis, MO Joyce Wu, MD; University of California, Los Angeles, CA Raymond Yeung, MD; University of Washington, Seattle, WA REFERENCES 1. 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