TSC Alliance

Research program stimulates and supports basic, translational, and clinical research on the various manifestations of Tuberous Sclerosis complex (TSC) to further the development of clinical therapies and, ultimately, a cure for TSC. Directed by steven l. roberds, phd, chief scientific officer, the TSC Alliance research program builds and fosters collaborations between basic and clinical researchers by collecting and distributing TSC natural history data and biosamples, through collaborative preclinical and clinical research programs, and by hosting biennial international TSC research conferences.since 1984, the TSC Alliance has invested more than $37 million into TSC research projects through grants and contracts: $20.6 million in research grants and postdoctoral fellowships, $5.3 million into the natural history database and biosample repository, $9.6 million into the preclinical consortium, and $1.6 million into the clinical research consortium. Grant and fellowship applications are reviewed in a three-step process: (1) all applications are reviewed by a committee comprised of scientists knowledgeable about the topic area for scientific merit and of caregivers or adults affected by TSC for potential impact on the lives of those affected by TSC; (2) the science and medical committee of the board of directors evaluates the grant review committee's recommendations and the relevance of the applications to the TSC Alliance's funding priorities; and (3) the board of directors then reviews the recommendations of the science and medical committee and makes final approval for funding. For a complete list of currently funded projects and an archive of past awardees, please visit tscalliance.org/grants.in 2023, the TSC Alliance hosted our biennial international TSC research conference: fueling the future. Fifteen percent of attendees self-identified as members of groups historically underrepresented in biomedical research. The conference featured an early career research symposium, a keynote speech from dr. martina bebin, 30 oral presentations, 59 posters, a TSC international workshop, and a combined closing session with TSC & lam regional conference participants. The conference also featured four breakout working group sessions (transition from pediatric to adult, neurodevelopment and early intervention, cellular energetics and metabolism, and big data and single cell approaches/analysis) to allow time for attendees to meet with others in their field and work toward solutions for current issues in their area.implemented in 2006, the TSC natural history database (nhd) captures clinical data to document the impact of the disease on a person's health over his/her lifetime. The database serves as a resource of information that helps TSC researchers better understand the progression of the disease, design hypothesis-driven questions to hasten the discovery of new treatments and identify persons with TSC who are eligible to participate in research studies. As of december 2023, 2,678 people with TSC were enrolled in the project from among 22 TSC clinic sites and through the TSC Alliance. The TSC Alliance provides funding to participating clinics to perform data entry, monitors the integrity of the database, and makes data available to investigators to answer specific research questions and identify potential participants for clinical trials and studies building upon the natural history database, the TSC biosample repository is a TSC alliance-directed project initiated in 2014 that will impact research over the next 10 years or more. The TSC Alliance's science and medical committee identified this as a gap that can only be filled effectively with leadership of the TSC Alliance, guided by a steering committee of clinicians and researchers. High-quality biosamples such as blood, dna, and tissues linked to detailed clinical data are critical for researchers to understand why TSC is so different from person to person. Samples in the repository are linked to detailed clinical data in our existing TSC natural history database and are available to qualified researchers worldwide. Samples are housed at and distributed from the van andel institute in grand rapids, mi, under control of the TSC Alliance. As of december 31, 2023, the TSC biosample repository has acquired 2,654 biosamples: 1012 blood samples from individuals with TSC enrolled in the nhd, 452 buccal samples from individuals with TSC enrolled in the nhd, 197 tissue samples from individuals with TSC enrolled in the nhd, 591 blood samples from the TSC clinical research consortium collaborative projects, 389 dna samples from the TSC autism center of excellence network autism biomarker study, and 10 control samples. The organization continues to grow the biosample repository by collecting blood samples annually from participants who volunteer to do so, enabling researchers to study changes in proteins and other molecules in the blood over time; adding additional TSC clinics as participating biosample repository collection sites; and collecting blood using mobile phlebotomy, enabling people to donate samples regardless of where they live in the us and whether they are seen at a TSC clinic. Since the inception of our mobile phlebotomy initiative, we have acquired 473 blood samples via mobile phlebotomy. To encourage and enable more researchers to utilize biosamples, the TSC Alliance awarded three seed grants in 2023, totaling $60,000, to labs that submitted meritorious and innovative ideas for research on TSC biosamples.the TSC Alliance's whole-genome sequencing (wgs) initiative using dna from blood samples in our biosample repository sequenced an additional 72 samples in 2023, totaling 115 samples since inception. This initiative supports clinical validation of variants found via wgs in either the tsc1 or tsc2 gene, and genetic results are offered back to participants along with a genetic counseling session free of charge to the family to help them better understand their unique TSC diagnosis and provide valuable information for future decision making such as family planning.in december 2021, the TSC Alliance added the TSC self-report portal to the TSC natural history database. This portal permits the collection of patient-reported outcomes on how TSC affects individuals and families, which will complement medical data in the natural history database. The purpose of this initiative is to help the TSC Alliance and TSC researchers better understand the perspective of those affected by TSC to develop tools to measure improvement in areas most important to the TSC community. Eventually, these measurements can be used to identify endpoints for clinical trials and evidence-based guidelines for treatment.one of the most impactful aspects of TSC on the quality of life for people living with TSC is tsc-associated neuropsychiatric disorders (tand). Therefore, the TSC Alliance's first use of the portal is through collaboration with the tandem project (empowering families through technology: a mobile-health project to reduce the tand identification and treatment gap) by allowing the community to complete the self-quantified tand checklist (tand-sq). At the end of 2023, 105 individuals were enrolled through the self-report portal.the TSC Alliance launched the TSC preclinical consortium in 2015 to help advance more drug candidates into clinical testing. To achieve this end, the preclinical consortium provides the infrastructure to foster collaboration between academia and pharmaceutical industry researchers and for access to resources designed to help facilitate drug development in TSC. Collaborating with the TSC community, the consortium has identified and implemented robust and reproducible cell and animal models for TSC manifestations including tumors, epilepsy, and tand. In 2022, the TSC Alliance entered into a partnership with the lam foundation to add lam mouse models to the preclinical consortium. The TSC Alliance has licenses to use specific TSC mouse models for experiments carried out by the preclinical consortium, and all mouse license agreements include the rights for the TSC Alliance to perform experiments under contract for commercial entities. This ensures data generated by the preclinical consortium can be used to accelerate the development of new treatments by commercial entities as well as academic investigators. Experiments are executed at partnering research institutions to ensure consistency in testing, data acquisition and interpretation. Epilepsy studies are conducted at psychogenics (us), and the tumor graft model and cell-based assays are conducted at porsolt (france). The van andel research institute, a non-profit research organization, maintains a colony of tsc2+/- aj mice and f l7-cre-tsc2 mice on behalf of the preclinical consortium.

Government relations efforts focus on increasing federal and state appropriations for TSC research, raising awareness, and collaborating with government partners to drive TSC research forward and improve clinical care and treatment options for individuals with TSC. On the state level, the TSC Alliance advocated for state funding for TSC centers in Alabama, Missouri, and Maryland, resulting in at least $1.25 million in state appropriations. The annual TSC Alliance march on capitol hill to advocate for federal funding for the Tuberous Sclerosis complex research program (tscrp) at the department of defense's (dod) congressionally directed medical research program (cdmrp) took place in early march 2023. Advocates met with more than 322 congressional offices virtually and in person to ask for $10 million in funding for the tscrp. The house tscrp dear colleague letter sponsored by representatives fitzpatrick (r-pa) and raskin (d-md) closed with 191signers. The senate letter sponsored by senators cramer (r-nd) and heinrich (d-nm) closed with 41 signers. Total funding for the tscrp has been $113 million since 2002, including a $10 million appropriation for fy234. Research performed through this program has recently led to additional clinical trials including determining if imatinib, a drug fda-approved for cancer, can safely improve levels of vegf-d, a biomarker of lymphangioleiomyomatosis (lam), a life-threatening lung manifestation of TSC, funded in fy2013; two tscrp awards in fy2012 and fy2015 that enabled generation of a potential approach for gene therapy of TSC, which has shown promising results in a mouse model of TSC tumors in the brain; a multi-site clinical trial testing the efficacy of an experimental topical rapamycin cream to treat the disfiguring facial tumors, called facial angiofibromas, caused by TSC funded in fy2010 that led the third fda-approved drug to treat TSC in april 2022; and a clinical research network that was created to test potential new therapies, to validate biomarkers, and to learn the natural history of leading to a clinical trial funded in fy2012. Data obtained from an fy2010 tscrp clinical research award to define early autism predictors in TSC and an fy2014 tscrp award for a pilot clinical trial is being tested in a large, nih-funded clinical trial looking at the effectiveness of a behavioral intervention strategy, jasper, to improve outcomes in children with autism. The tscrp has also funded research to develop animal models of TSC that have seizures, enabling a better understanding of the etiology of TSC. Based on data from tscrp-funded animal models of TSC that have seizures and share pathology related to that of traumatic brain injury, an industry-sponsored clinical trial demonstrated the effectiveness the mtor inhibitor, everolimus, at treating epilepsy in many individuals with TSC. None of this progress would have been possible without the critical support provided through the tscrp.global outreach works to address unmet needs within the global TSC community. The program provides the opportunity for the TSC Alliance to share experiences and assist in the start-up of support of tsc-related organizations in other countries. A global Alliance is a structured group of empowered and caring volunteers who work closely with the TSC Alliance to facilitate local connections for individuals and families affected by TSC and raise revenue and awareness while supporting the mission of the organization. The TSC Alliance has six global partnerships, including TSC Alliance of israel, ts canada st, TSC Alliance of mexico, TSC Alliance foundation (in thailand), hungarian foundation for Tuberous Sclerosis, and TSC Alliance of india. The TSC Alliance recognizes 13 TSC clinics in global Alliance countries. Professional education expands programs to target researchers and healthcare providers caring for individuals with TSC, medical students, genetic counselors and educators to minimize the consequences of ignorance and misinformation. The TSC Alliance exhibited at the american epilepsy society annual meeting. Staff members and a volunteer shared educational materials with attendees who visited the booth. Staff also participated in the TSC special interest group session, and the TSC Alliance hosted more than 100 people at a reception with presentations by parents of a child with TSC and by dr. angelique bordey, who described how TSC Alliance has impacted her research. The TSC Alliance participated in or presented at 26 professional meetings in 2023 including pretola course, research america annual advocacy awards, women at bridge leadership speaking series, insitro town hall, rare disease innovation and partnering summit, anya's accelerator workshop, nord, TSC Alliance mexico briefing, ean congressional briefing, ats annual meeting, interagency collaborative to advance research in epilepsy (icare), rare diseases international world health assembly, ucp annual conference, marinus town hall, tandem mini symposium, etsc workshop, ninds nonprofit forum, crisis intervention training international, tsci workshop, TSC reproductive & perinatal task force meeting, lgs meeting, global genes rare summit, pcori annual meeting, apertura town hall, rdcrn fall meeting, aes, and ean briefing.