Molecular therapies for tuberous sclerosis and neurofibromatosis.

Abstract

Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal-dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions.

• Authors: David Neal Franz, Brian D Weiss
• Journal: Current neurology and neuroscience reports (Curr Neurol Neurosci Rep) Vol. 12 Issue 3 Pg. 294-301 (Jun 2012) ISSN: 1534-6293 [Electronic] United States
• PMID: 22544507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Humans
• Neurofibromatosis 1 (genetics, metabolism, therapy)
• Signal Transduction (genetics)
• TOR Serine-Threonine Kinases (metabolism)
• Tuberous Sclerosis (genetics, metabolism, therapy)