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The Ultimated Edition to the Mountdomain THEULTIMATED EDITIONUS 20170247762A1 TO THE MOUNTDOMAIN ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0247762 A1 Heiman ( 43 ) Pub . Date: Aug . 31 , 2017 ( 54 ) COMPOSITIONS , METHODS AND USE OF Publication Classification SYNTHETIC LETHAL SCREENING (51 ) Int . CI. C120 1 /68 ( 2006 . 01 ) (71 ) Applicants : THE BOARD INSTITUTE INC ., C12N 15 / 113 ( 2006 .01 ) Cambridge, MA (US ) ; Massachusetts COZK 16 / 40 ( 2006 .01 ) Institute of Technology , Cambridge , A01K 67 /027 (2006 . 01 ) C12N 9 / 22 ( 2006 . 01 ) MA (US ) (52 ) U . S . CI. CPC . .. C12Q 1 /6883 (2013 . 01) ; A01K 67 /0278 (72 ) Inventor : Myriam Heiman , Newton , MA (US ) ( 2013 .01 ) ; C12N 9 / 22 ( 2013 .01 ) ; CO7K 16 / 40 ( 2013 .01 ) ; C12Y 111 /01009 ( 2013 . 01 ) ; C12N (21 ) Appl. No. : 15 /521 , 780 15 / 113 (2013 .01 ) ; AOIK 2267 / 0318 ( 2013 .01 ) ; C12Q 2600 / 118 ( 2013 . 01 ) ; C12Q 2600 / 158 (22 ) PCT Filed : Oct . 27 , 2015 (2013 .01 ) ; C120 2600 / 136 (2013 .01 ) ; C12N ( 86 ) PCT No. : PCT/ US2015 / 057567 2310 / 20 ( 2017 .05 ) ; CO7K 2317 / 34 (2013 .01 ) $ 371 ( C ) ( 1 ), (57 ) ABSTRACT Apr. 25 , 2017 The present invention generally relates to methods of iden ( 2 ) Date : tifying modulators of central nervous system diseases and the use of the modulators in treatment and diagnosis . The methods utilize a novel high throughput screen that includes Related U . S . Application Data injection of a library of barcoded viral vectors expressing (60 ) Provisional application No . 62/ 122, 686 , filed on Oct. shRNA ' s , CRISPR / Cas systems or cDNA ' s into animal 27 , 2014 . models of disease and detecting synthetic lethality . 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US 2017 /0247762 A1 Aug. 31, 2017 COMPOSITIONS , METHODS AND USE OF very difficult . Mental abilities generally decline into demen SYNTHETIC LETHAL SCREENING tia . Complications such as pneumonia , heart disease , and physical injury from falls reduce life expectancy to around RELATED APPLICATIONS AND twenty years from the point at which symptoms begin . There INCORPORATION BY REFERENCE is no cure for Huntington ' s disease , and full- time care is [ 0001] This application claims benefit of and priority to required in the later stages of the disease. U . S . provisional patent application Ser. No . 62 /122 ,686 , [ 0008 ] Treatments for Huntington ' s disease are available filed Oct. 27 , 2014 . to reduce the severity of some of its symptoms ( Frank et al . , [ 0002 ] The foregoing applications, and all documents (2010 ) Drugs 70 ( 5 ): 561 -71 ) . Tetrabenazine was approved cited therein or during their prosecution ( " appln cited docu in 2008 for treatment of chorea in Huntington ' s disease in ments” ) and all documents cited or referenced in the appln the United States . Other drugs that help to reduce chorea cited documents , and all documents cited or referenced include neuroleptics and benzodiazepines . Compounds such herein (“ herein cited documents ” ) , and all documents cited as amantadine are still under investigation but have shown or referenced in herein cited documents , together with any preliminary positive results (Walker , ( 2007 ) Lancet 369 manufacturer ' s instructions , descriptions, product specifica ( 9557 ) : 218 - 28 ) . Hypokinesia and rigidity , especially in tions , and product sheets for any products mentioned herein juvenile cases, can be treated with anti -Parkinson drugs , and or in any document incorporated by reference herein , are myoclonic hyperkinesia can be treated with valproic acid . hereby incorporated herein by reference , and may be employed in the practice of the invention . More specifically , [00091 Huntington ' s disease is caused by a mutation in the all referenced documents are incorporated by reference to Huntingtin gene . Expansion of a CAG ( cytosine - adenine the same extent as if each individual document was specifi guanine ) triplet repeat stretch within the Huntingtin gene cally and individually indicated to be incorporated by ref results in a mutant form of the protein , which gradually damages cells in the brain , through mechanisms that are not erence . fully understood . The length of the trinucleotide repeat FEDERAL FUNDING LEGEND accounts for 60 % of the variation in the age symptoms appear and the rate they progress. The remaining variation is [0003 ) This invention was made with government support due to environmental factors and other genes that influence under grant number NS085880 awarded by the National the mechanism of the disease (Walker , ( 2007) Lancet 369 Institutes of Health . The government has certain rights in the (9557 ) : 218 - 28 ) . invention . [ 0010 ] The diagnosis of Huntington ' s disease is suspected FIELD OF THE INVENTION clinically in the presence of symptoms. The diagnosis can be confirmed through molecular genetic testing which identi [ 0004 ] The present invention generally relates to methods fies the expansion in the Huntingtin gene . Testing of adults of identifying modulators of central nervous system diseases at risk for Huntington disease who have no symptoms using a novel high throughput methodology that includes (asymptomatic ) of the disease has been available for over expressing CRISPR / Cas systems, shRNA ' s or cDNA ' s in ten years . However , this testing cannot accurately predict the animal models of disease . age a person found to carry a Huntington disease causing mutation will begin experiencing symptoms, the severity or BACKGROUND OF THE INVENTION type of symptoms they will experience , or rate of disease [0005 ] Currently there are no cures or effective treatments progression . Other markers for disease progression are for many neurodegenerative diseases . All of the major available , for example , loss of DARPP - 32 striatal expression neurodegenerative diseases display characteristic
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