Statins as Treatment for Cognitive Dysfunction Associated with RASopathies
• Statins would represent the first and only drug available to treat the cognitive defects observed in NF1, Noonan and other RASopathies• Statins have already been approved by the FDA as a cholesterol-lowering drug, demonstrating an amenable safety profile in humans• Effectiveness in restoring cognitive function has been demonstrated in vivo
• Treatment of cognitive dysfunction associated with NF1• Treatment of cognitive dysfunction associated with Noonan syndrome• Treatment of other disorders driven by hyperactivation of the Ras-MAPK pathway
Professor Alcino Silva and colleagues at the UCLA department of Neurobiology have repurposed HMG-CoA reductase inhibitors (or statins) to reverse the cognitive dysfunction associated with RASopathies. By blocking HMG-CoA reductase, the drug prevents overactivation of the Ras protein, which leads to deficits in long term potentiation, a mechanism of learning and memory. Using in vivo models of NF1 and Noonan Syndrome, the researchers have shown that lovastatin is able to restore both LTP deficits and cognitive function to wild-type levels.
Patent Number: US8222293B2
Application Number: US2006569426A
Inventor: Silva, Alcino | Cui, Yijun | Li, Weldong | Kushner, Steven A.
Priority Date: 24 May 2004
Priority Number: US8222293B2
Application Date: 20 Nov 2006
Publication Date: 17 Jul 2012
IPC Current: A61K003135 | A61K0031366 | A61K0031401 | A61K003147
US Class: 514460 | 514307
Assignee Applicant: The Regents of the University of California
Title: Treating learning deficits with inhibitors of Hmg CoA reductase
Usefulness: Treating learning deficits with inhibitors of Hmg CoA reductase
Summary: For treating cognitive deficit associated with (e.g. Down's syndrome, Angelman syndrome, NF-1 genetic defect, genetic defect in OPHN1, tuberous sclerosis, autism, attention deficit/hyperactivity disorder, dysregulation of small monomeric GTP binding protein activity (such as RAS protein associated with NF-1 genetic effect), dysregulation of mitogen activated protein kinase (MAPK) signaling pathway, increased inhibitory neuronal activity, increased GABA-mediated inhibition and activity of GABA-A/B) in a subject with normal cholesterol level; and for modulating long term potentiation (LTP) in a neutral system (such as CA1 region of hippocampus) with a depressed LTP response associated with the dysregulation of small monomeric GTP binding protein activity, MAPK signaling pathway or inhibitory neuronal activity that is associated with increased GABA-mediated inhibition (claimed). Also useful for treating memory and learning deficits.
Novelty: Pharmaceutical composition useful for treating cognitive deficit associated with, e.g. Down's syndrome comprises hydroxymethylglutaryl Co-enzyme A reductase inhibitor
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8222293
State Of Development The researchers first demonstrated the ability of statins to restore cognitive function in a mouse model of NF1. More recently, a phase I clinical trial demonstrated that lovastatin is safely tolerated in children, with provisional results from the same trial indicating some improvements in memory. Research adequately powered to fully assess therapeutic effects is ongoing in a phase II, multi-institutional protocol. Background RASopathies comprise a group of developmental syndromes arising from germline mutations in genes resulting in dysregulation of the Ras-MAPK signaling pathway. Among the RASopathies, Noonan syndrome and neurofibromatosis type 1 (NF1) alone account for an estimated 9 million cases worldwide. In addition to the physical symptoms associated with these diseases, physicians also observe cognitive defects, with patients exhibiting a decreased capacity to learn and form memories. Families with NF1 patients cite these as the most pernicious part of this disorder, and there are currently no treatments available to alleviate this cognitive dysfunction. Related Materials Additional Technologies by these Inventors Tech ID/UC Case 20191/2004-598-0 Related Cases 2004-598-0
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