IP Library › Granted Patent US 12,215,382
Granted Patent B2
US 12,215,382 · App. 16/807,125 · Granted Feb 4, 2025

Liver protective MARC variants and uses thereof

Inventors: Sekar Kathiresan (Boston, MA); Connor Emdin (Boston, MA)
Assignee: The General Hospital Corporation
C12Q1/6858A61K31/7088A61K31/713A61K45/06C12Q2600/158
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,215,382
App. No.
16/807,125
Granted
Feb 4, 2025
Kind
B2
Abstract

Described herein are MARC variants that associate with a risk of liver diseases or a symptom(s) thereof, such as cirrhosis, or protection against such liver diseases or symptom(s) thereof. Also described herein are compositions and formulations that can be capable of modulating MARC in a subject and/or treatment of a liver disease or a symptom thereof.

Claims (26)

1. A method of making a protective modification of a MARC1 gene in a subject comprising:

detecting a MARC1 protein variant or a MARC1 protein variant-encoding polynucleotide in the subject, wherein the MARC1 protein variant comprises alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; and

administering, to the subject thereof having the MARC1 protein variant or the MARC1 protein variant-encoding polynucleotide, a programmable nuclease-based system comprising a nuclease or a guide polynucleotide each configured to bind a target polynucleotide, wherein the target polynucleotide is the MARC1 protein variant-encoding polynucleotide, and

wherein the programmable nuclease-based system is configured to modify the MARC1 protein variant-encoding polynucleotide from the alanine at the position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1 to a threonine, thereby making a protective modification of the MARC1 gene in the subject.

2. The method of claim 1 , wherein the subject has a liver disease or symptom thereof.

3. The method of claim 2 , wherein the liver disease or symptom thereof comprises alcoholic cirrhosis, non-alcoholic cirrhosis, a hepatitis-related cirrhosis, hepatic steatosis, alcohol-related fatty liver disease (ALD), or nonalcoholic fatty liver disease (NAFLD).

4. The method of claim 1 , wherein the subject has an elevated amount, activity of, or both of or one or more of aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol, low-density lipoprotein (LDL) cholesterol, or a combination thereof as compared to a subject having threonine at position 165 of MARC1 prior to administration.

5. The method of claim 1 , wherein the protective modification of the MARC1 gene produces in the subject a decrease in:

(a) an amount of, activity of, or both of aminotransferase (ALT), alkaline phosphatase (ALP), or any combination thereof in the subject;

(b) an amount of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, or any combination thereof in the subject; or

(c) both (a) and (b).

6. The method of claim 1 , wherein the subject is

a) heterozygous for a MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; or

b) homozygous for the MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1.

7. A method of reducing total cholesterol, low-density lipoprotein, or a combination thereof in a subject thereof, comprising:

detecting a MARC1 protein variant or a MARC1 protein variant-encoding polynucleotide in the subject, wherein the MARC1 protein variant comprises alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; and

administering to the subject having the MARC1 protein variant or the MARC1 protein variant-encoding polynucleotide a programmable nuclease-based system comprising a nuclease or a guide polynucleotide each configured to bind a target polynucleotide, wherein the target polynucleotide is the MARC1 protein variant-encoding polynucleotide,

wherein the programmable nuclease-based system is configured to modify the MARC1 protein variant-encoding polynucleotide, wherein the modification comprises modifying the alanine at the position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1 to a threonine, thereby reducing total cholesterol, low-density lipoprotein, or a combination thereof in the subject.

8. The method of claim 7 , wherein the subject is

a) heterozygous for a MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; or

b) homozygous for the MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1.

9. The method of claim 8 , wherein

the MARC1 protein variant is SEQ ID NO: 22.

10. The method of claim 7 , wherein the subject has an elevated amount, activity of, or both of or one or more of aminotransferase (ALT), alkaline phosphatase (ALP), or a combination thereof prior to administration.

11. The method of claim 7 , wherein the subject has a liver disease or a symptom thereof, wherein the liver disease is selected from the group consisting of: alcoholic cirrhosis, non-alcoholic cirrhosis, a hepatitis-related cirrhosis, hepatic steatosis, alcohol-related fatty liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD).

12. The method of claim 1 , wherein the MARC1 protein variant is SEQ ID NO: 22.

Assignments (3)
CONFIRMATORY LICENSE Recorded Oct 2, 2023
From: BROAD INSTITUTE, INC.
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065091/0180 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 13, 2022
From: KATHIRESAN, SEKAR
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 059585/0254 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 13, 2022
From: EMDIN, CONNOR
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 059585/0333 →
Continuity (2)
Provisional Application 62812881 · Mar 1, 2019
Related Publication 20210262022A1 · Aug 26, 2021
References Cited (400)
US 4797368A · Carter et al. · 1989 [cited by applicant]
US 4873316A · Meade et al. · 1989 [cited by applicant]
US 5173414A · Lebkowski et al. · 1992 [cited by applicant]
US 5543158A · Gref et al. · 1996 [cited by applicant]
US 5563055A · Townsend et al. · 1996 [cited by applicant]
US 5789156A · Bujard et al. · 1998 [cited by applicant]
US 5814618A · Bujard et al. · 1998 [cited by applicant]
US 5846946A · Huebner et al. · 1998 [cited by applicant]
US 5855913A · Hanes et al. · 1999 [cited by applicant]
US 5985309A · Edwards et al. · 1999 [cited by applicant]
US 6007845A · Domb et al. · 1999 [cited by applicant]
US 6268490B1 · Imanishi et al. · 2001 [cited by applicant]
US 6479626B1 · Kim et al. · 2002 [cited by applicant]
US 6525191B1 · Ramasamy et al. · 2003 [cited by applicant]
US 6534261B1 · Cox et al. · 2003 [cited by applicant]
US 6602858B2 · Beigelman et al. · 2003 [cited by applicant]
US 6607882B1 · Cox et al. · 2003 [cited by applicant]
US 6670461B1 · Wengel et al. · 2003 [cited by applicant]
US 6746838B1 · Choo et al. · 2004 [cited by applicant]
US 6750059B1 · Blakesley et al. · 2004 [cited by applicant]
US 6794136B1 · Eisenberg et al. · 2004 [cited by applicant]
US 6794499B2 · Wengel et al. · 2004 [cited by applicant]
US 6824978B1 · Cox et al. · 2004 [cited by applicant]
US 6866997B1 · Choo et al. · 2005 [cited by applicant]
US 6903185B2 · Kim et al. · 2005 [cited by applicant]
US 6933113B2 · Case et al. · 2005 [cited by applicant]
US 6979539B2 · Cox et al. · 2005 [cited by applicant]
US 6998484B2 · Koch et al. · 2006 [cited by applicant]
US 7013219B2 · Case et al. · 2006 [cited by applicant]
US 7030215B2 · Liu et al. · 2006 [cited by applicant]
US 7034133B2 · Wengel et al. · 2006 [cited by applicant]
US 7053207B2 · Wengel et al. · 2006 [cited by applicant]
US 7084125B2 · Wengel et al. · 2006 [cited by applicant]
US 7220719B2 · Case et al. · 2007 [cited by applicant]
US 7241573B2 · Choo et al. · 2007 [cited by applicant]
US 7241574B2 · Choo et al. · 2007 [cited by applicant]
US 7259015B2 · Kingsman et al. · 2007 [cited by applicant]
US 7303910B2 · Bebbington et al. · 2007 [cited by applicant]
US 7351585B2 · Mitrophanous et al. · 2008 [cited by applicant]
US 7399845B2 · Seth et al. · 2008 [cited by applicant]
US 7427672B2 · Imanishi et al. · 2008 [cited by applicant]
US 7569686B1 · Bhat et al. · 2009 [cited by applicant]
US 7585849B2 · Liu et al. · 2009 [cited by applicant]
US 7595376B2 · Kim et al. · 2009 [cited by applicant]
US 7741457B2 · Seth et al. · 2010 [cited by applicant]
US 7776321B2 · Cascalho et al. · 2010 [cited by applicant]
US 8021867B2 · Smith et al. · 2011 [cited by applicant]
US 8022193B2 · Seth et al. · 2011 [cited by applicant]
US 8030467B2 · Seth et al. · 2011 [cited by applicant]
US 8044019B2 · Uno et al. · 2011 [cited by applicant]
US 8071082B2 · Zugates et al. · 2011 [cited by applicant]
US 8097710B2 · Baulcombe et al. · 2012 [cited by applicant]
US 8101348B2 · Tuschl et al. · 2012 [cited by applicant]
US 8119361B2 · Smith et al. · 2012 [cited by applicant]
US 8119381B2 · Smith et al. · 2012 [cited by applicant]
US 8124369B2 · Smith et al. · 2012 [cited by applicant]
US 8129134B2 · Smith et al. · 2012 [cited by applicant]
US 8133697B2 · Smith et al. · 2012 [cited by applicant]
US 8163514B2 · Smith et al. · 2012 [cited by applicant]
US 8278283B2 · Seth et al. · 2012 [cited by applicant]
US 8278425B2 · Prakash et al. · 2012 [cited by applicant]
US 8278426B2 · Seth et al. · 2012 [cited by applicant]
US 8314227B2 · Wengel et al. · 2012 [cited by applicant]
US 8372951B2 · Chang et al. · 2013 [cited by applicant]
US 8404658B2 · Hajjar et al. · 2013 [cited by applicant]
US 8454972B2 · Nabel et al. · 2013 [cited by applicant]
US 8575305B2 · Gait et al. · 2013 [cited by applicant]
US 8614194B1 · Chen et al. · 2013 [cited by applicant]
US 8709843B2 · Shakuda et al. · 2014 [cited by applicant]
US 8945839B2 · Zhang et al. · 2015 [cited by applicant]
US 9301923B2 · Baryza et al. · 2016 [cited by applicant]
US 10076536B2 · Kole et al. · 2018 [cited by applicant]
US 10835581B2 · Gladwin · 2020 [cited by applicant]
US 20020150626A1 · Kohane et al. · 2002 [cited by applicant]
US 20040013648A1 · Kingsman et al. · 2004 [cited by applicant]
US 20040142476A1 · Evans et al. · 2004 [cited by applicant]
US 20040171156A1 · Hartley et al. · 2004 [cited by applicant]
US 20040171570A1 · Allerson et al. · 2004 [cited by applicant]
US 20050019923A1 · Uchegbu et al. · 2005 [cited by applicant]
US 20050123596A1 · Kohane et al. · 2005 [cited by applicant]
US 20050244858A1 · Rossi et al. · 2005 [cited by applicant]
US 20060281180A1 · Radcliffe et al. · 2006 [cited by applicant]
US 20070025970A1 · Kingsman et al. · 2007 [cited by applicant]
US 20070054961A1 · Maden et al. · 2007 [cited by applicant]
US 20080039618A1 · Allerson et al. · 2008 [cited by applicant]
US 20080267903A1 · Uchegbu et al. · 2008 [cited by applicant]
US 20090007284A1 · Radcliffe et al. · 2009 [cited by applicant]
US 20090012281A1 · Swayze et al. · 2009 [cited by applicant]
US 20090017543A1 · Wilkes et al. · 2009 [cited by applicant]
US 20090111106A1 · Mitrophanous et al. · 2009 [cited by applicant]
US 20100129793A1 · Mirkin et al. · 2010 [cited by applicant]
US 20100317109A1 · Maden et al. · 2010 [cited by applicant]
US 20110027239A1 · Paek et al. · 2011 [cited by applicant]
US 20110117189A1 · Mazzone et al. · 2011 [cited by applicant]
US 20110201643A1 · Maier · 2011 [cited by examiner]
US 20110212179A1 · Liu et al. · 2011 [cited by applicant]
US 20110293571A1 · Widdowson et al. · 2011 [cited by applicant]
US 20110293703A1 · Mahon et al. · 2011 [cited by applicant]
US 20110313020A1 · Templin et al. · 2011 [cited by applicant]
US 20120157511A1 · Manoharan et al. · 2012 [cited by applicant]
US 20120295960A1 · Palfi et al. · 2012 [cited by applicant]
US 20130011922A1 · Quay et al. · 2013 [cited by applicant]
US 20130096289A1 · Wengel et al. · 2013 [cited by applicant]
US 20130185823A1 · Kuang et al. · 2013 [cited by applicant]
US 20130190383A1 · Vaish et al. · 2013 [cited by applicant]
US 20130244279A1 · De Fougerolles et al. · 2013 [cited by applicant]
US 20130245107A1 · De Fougerolles et al. · 2013 [cited by applicant]
US 20130252281A1 · De Fougerolles et al. · 2013 [cited by applicant]
US 20130302401A1 · Ma et al. · 2013 [cited by applicant]
US 20140287983A1 · Mourich et al. · 2014 [cited by applicant]
US 20140308304A1 · Manoharan et al. · 2014 [cited by applicant]
US 20140328759A1 · Cullis et al. · 2014 [cited by applicant]
US 20140348900A1 · Zhu et al. · 2014 [cited by applicant]
US 20150023288A1 · Vermani et al. · 2015 [cited by applicant]
US 20150071903A1 · Liu et al. · 2015 [cited by applicant]
US 20150105538A1 · Chromy et al. · 2015 [cited by applicant]
US 20150118216A1 · Liu et al. · 2015 [cited by applicant]
US 20150140070A1 · Heartlein et al. · 2015 [cited by applicant]
US 20150232883A1 · Dahlman et al. · 2015 [cited by applicant]
US 20150250725A1 · Bader et al. · 2015 [cited by applicant]
US 20150267202A1 · Iversen et al. · 2015 [cited by applicant]
US 20150291966A1 · Zhang et al. · 2015 [cited by applicant]
US 20160082126A1 · Wang et al. · 2016 [cited by applicant]
US 20160174546A1 · Berg et al. · 2016 [cited by applicant]
US 20160200779A1 · Liu et al. · 2016 [cited by applicant]
US 20160251398A1 · Weller et al. · 2016 [cited by applicant]
US 20160367686A1 · Anderson et al. · 2016 [cited by applicant]
US 20170051278A1 · Kole et al. · 2017 [cited by applicant]
US 20170079916A1 · Khan et al. · 2017 [cited by applicant]
US 20170166903A1 · Zhang et al. · 2017 [cited by applicant]
US 20180216111A1 · Wilton et al. · 2018 [cited by applicant]
US 20180271893A1 · Kole et al. · 2018 [cited by applicant]
US 20190015440A1 · Passini et al. · 2019 [cited by applicant]
US 20190177723A1 · Dickson et al. · 2019 [cited by applicant]
US 20190203212A1 · Zhang et al. · 2019 [cited by applicant]
US 20190352652A1 · Abudayyeh et al. · 2019 [cited by applicant]
US 20200241005A1 · Miner · 2020 [cited by examiner]
US 20220062385A1 · Gladwin · 2022 [cited by examiner]
EP 0264166A1 · 1988 [cited by applicant]
WO 9301294A1 · 1993 [cited by applicant]
WO 9324641A2 · 1993 [cited by applicant]
WO 9405700A3 · 1994 [cited by applicant]
WO 9839352A1 · 1998 [cited by applicant]
WO 1999007409A1 · 1999 [cited by applicant]
WO 1999032619A1 · 1999 [cited by applicant]
WO 9914226A3 · 1999 [cited by applicant]
WO 2000001846A2 · 2000 [cited by applicant]
WO 0047599A1 · 2000 [cited by applicant]
WO 2000044895A1 · 2000 [cited by applicant]
WO 2000044914A1 · 2000 [cited by applicant]
WO 2001029058A1 · 2001 [cited by applicant]
WO 2001036646A1 · 2001 [cited by applicant]
WO 2001075164A2 · 2001 [cited by applicant]
WO 2004083430A3 · 2004 [cited by applicant]
WO 2005105152A2 · 2005 [cited by applicant]
WO 2006069782A2 · 2006 [cited by applicant]
WO 2006047842A3 · 2006 [cited by applicant]
WO 2007121947A1 · 2007 [cited by applicant]
WO 2008042156A1 · 2008 [cited by applicant]
WO 2008042973A2 · 2008 [cited by applicant]
WO 2008049078B1 · 2008 [cited by applicant]
WO 2010061186A2 · 2010 [cited by applicant]
WO 2011005861A9 · 2011 [cited by applicant]
WO 2011028929A3 · 2011 [cited by applicant]
WO 2012135025A2 · 2012 [cited by applicant]
WO 2013036868A1 · 2013 [cited by applicant]
WO 2013046247A1 · 2013 [cited by applicant]
WO 2013093648A2 · 2013 [cited by applicant]
WO 2014018423A2 · 2014 [cited by applicant]
WO 2014093622A2 · 2014 [cited by applicant]
WO 2014118272A1 · 2014 [cited by applicant]
WO 2014186366A1 · 2014 [cited by applicant]
WO 2015082080A1 · 2015 [cited by applicant]
WO 2015086795A1 · 2015 [cited by applicant]
WO 2015089419A2 · 2015 [cited by applicant]
WO 2016025131A1 · 2016 [cited by applicant]
WO 2016027264A1 · 2016 [cited by applicant]
WO 2016073433A1 · 2016 [cited by applicant]
WO 2016099887A1 · 2016 [cited by applicant]
WO 2016100272A1 · 2016 [cited by applicant]
WO 2016100562A1 · 2016 [cited by applicant]
WO 2016100568A1 · 2016 [cited by applicant]
WO 2016100571A1 · 2016 [cited by applicant]
WO 2016106236A1 · 2016 [cited by applicant]
WO 2016161516A1 · 2016 [cited by applicant]
WO 2017019867A1 · 2017 [cited by applicant]
WO 2017066175A1 · 2017 [cited by applicant]
WO 2017062835A3 · 2017 [cited by applicant]
WO 2017100158A1 · 2017 [cited by applicant]
WO 2017105991A1 · 2017 [cited by applicant]
WO 2017106414A1 · 2017 [cited by applicant]
WO 2018000580A1 · 2018 [cited by applicant]
WO 2018213708A1 · 2018 [cited by applicant]
WO 2018213726A1 · 2018 [cited by applicant]
WO 2019005884A1 · 2019 [cited by applicant]
WO 2019005886A1 · 2019 [cited by applicant]
WO 2019018423A1 · 2019 [cited by applicant]
WO 2019059973A1 · 2019 [cited by applicant]
WO 2019071048A1 · 2019 [cited by applicant]
WO 2019126709A1 · 2019 [cited by applicant]
WO 2019126716A1 · 2019 [cited by applicant]
WO 2019126762A2 · 2019 [cited by applicant]
WO 2020033601A1 · 2020 [cited by applicant]
WO 2020131862A1 · 2020 [cited by applicant]
Emdin et al., A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease, PLoS Genetics, vol. 16(4):e1008629, pp. 1-16. (Year: 2020). [cited by examiner]
Janik et al., MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis, Scientific Reports, vol. 11:24407, pp. 1-10. (Year: 2021). [cited by examiner]
Sato et al., Suppressive effect of the histone deacetylase inhibitor subreroylanilide hydroxamic acid (SAHA) on hepatitis C virus replication, Journal of Cellular Biochemistry, vol. 114, pp. 1987-1996. (Year: 2013). [cited by examiner]
Eslam et al., Genetics and epigenetics of NAFLD and NASH: Clinical impact, Journal of Hepatology, vol. 68, pp. 268-279. (Year: 2018). [cited by examiner]
Namjou et al., GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE network, BMC Medicine, vol. 17:135, pp. 1-19. (Year: 2019). [cited by examiner]
Willer et al. (of Global Lipids Genetics Consortium), published in 2013, Discovery and refinement of loci associated with lipid levels, Nature Genetics 45(11):1274-1283, and supplementary information available at https:… [cited by applicant]
Teslovich et al., published in 2010, Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids, Nature 466 (7307):707-713. [cited by applicant]
Abul-Husn et al., published in 2018, A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease, The New England Journal of Medicine 378(12):1096-1106, and supplementary material available at https:… [cited by applicant]
Emdin et al., published in 2019, A missense variant in Mitochondrial Amidoxime Reducing 4 Component 1 gene and protection against liver disease, available at bioRxiv preprint doi: https//doi.org/10.1101/594523. [cited by applicant]
Wilkins et al., published in 2013, Nonalcoholic Fatty Liver Disease: Diagnosis and Management, 5 Am. Fam. Physician 88(1):35-42. [cited by applicant]
Martin et al., published in 2007, Genetic association meets RNA interference: large-scale genomic screens for causation and mechanism of complex diseases, Pharmacogenomics 8(5):455-464. [cited by applicant]
“Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease”, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, The New England Journal of Medicine, vol. 374, No. 12, Mar. 20… [cited by applicant]
Abe, et al., “The Development of CRISPR for a Mollusc Establishes the Formin Lsdia1 as the Long-Sought Gene for Snail Dextral/sinistral Coiling”, Development, vol. 147, 2020, 8 pages. [cited by applicant]
About, et al., “HCV-Associated Liver Fibrosis and HSD17B13”, The New England Journal of Medicine, vol. 379, No. 19, Nov. 8, 2018, 1875-1876. [cited by applicant]
Abul-Husn, et al., “A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease”, The New England Journal of Medicine, vol. 387, No. 12, Mar. 22, 2018, 1096-1106. [cited by applicant]
Alba, et al., “Gutless Adenovirus: Last-Generation Adenovirus for Gene Therapy”, Gene Therapy, vol. 12, 2005, S18-S27. [cited by applicant]
Alhasan, “Exosome Encased Spherical Nucleic Acid Gold Nanoparticle Conjugates As Potent MicroRNA Regulation Agents”, Small, vol. 10, Issue 1, Jan. 15, 2014, 14 pages. [cited by applicant]
Allart, et al., “1,5-Anhydro-2-Deoxy-D-Altritol Oligonucleotides as Conformationally Restricted Analogues of Rna”, Nucleosides and Nucleotides , vol. 17, Issue 9-11, 1998, 1523-1526. [cited by applicant]
Allshire, “RNAi and Heterochromatin—a Hushed-Up Affair”, Science, vol. 297, Issue 5588, 2002, 1818-1819. [cited by applicant]
Altinoglu, et al., “Intracellular Delivery of the Pten Protein Using Cationic Lipidoids for Cancer Therapy”, Biomaterials Science, vol. 4, No. 12, 2016, 1773-1780. [cited by applicant]
Amalfitano, “Production and Characterization of Improved Adenovirus Vectors with the E1, E2b, and E3 Genes Deleted”, Journal of Virology, vol. 72, No. 2, 1998, 926-933. [cited by applicant]
Amann, et al., “Tightly Regulated Tuc Promoter Vectors Useful For the Expression of Unfused and Fused Proteins in [cited by applicant]
Anton, et al., “Visualization of Specific DNA Sequences in Living Mouse Embryonic Stem Cells With a Programmable Fluorescent CRISPR/Cas System”, Nucleus, vol. 5, No. 2, Mar./Apr. 2014, 163-172. [cited by applicant]
Anzalone, et al., “Search-and-replace Genome Editing Without Double-Strand Breaks or Donor DNA”, Nature, vol. 576, No. 7785, Dec. 5, 2019, 30 pages. [cited by applicant]
Atschul, et al., “Basic Local Alignment Search Tool”, Journal of Molecular Biology, vol. 215, 1990, 403-410. [cited by applicant]
Azzouz, et al., “Multicistronic Lentiviral Vector-Mediated Striatal Gene Transfer of Aromatic L-Amino Acid Decarboxylase, Tyrosine Hydroxylase, and GTP Cyclohydrolase I Induces Sustained Transgene Expression, Dopamine P… [cited by applicant]
Back, et al., “Neuron-Specific Genome Modification in the Adult Rat Brain Using CRISPR-Cas9 Transgenic Rats”, Neuron, vol. 102, Apr. 3, 2019, 105-119. [cited by applicant]
Bacon, et al., “Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Disease”, Hepatology, vol. 54, No. 1, 2011, 328-343. [cited by applicant]
Bahramian, et al., “Transcriptional and Posttranscriptional Silencing of Rodent α1(I) Collagen by a Homologous Transcriptionally Self-Silenced Transgene”, Molecular and Cellular Biology, vol. 19, No. 1, 1999, 274-283. [cited by applicant]
Balagaan, et al., “Stable and Efficient Intraocular Gene Transfer Using Pseudotyped EIAV Lentiviral Vectors”, The Journal of Gene Medicine, vol. 8, Issue 3, Mar. 2006, 275-285. [cited by applicant]
Balaggan, et al., “Ocular Gene Delivery Using Lentiviral Vectors”, Gene Therapy, vol. 19, 2012, 145-153. [cited by applicant]
Balague, et al., “Sustained High-Level Expression of Full-Length Human Factor VIII and Restoration of Clotting Activity in Hemophilic Mice Using a Minimal Adenovirus Vector”, Blood, vol. 95, No. 3, 2000, 820-828. [cited by applicant]
Baldari, et al., “A Novel Leader Peptide Which Allows Efficient Secretion of a Fragment of Human Interleukin 1β In [cited by applicant]
Banerji, et al., “A Lymphocyte-Specific Cellular Enhancer is Located Downstream of the Joining Region in Immunoglobulin Heavy Chain Genes”, Cell, vol. 33, Issue 3, Jul. 1983, 729-740. [cited by applicant]
Bartlett, et al., “Impact of Tumor-Specific Targeting on The Biodistribution and Efficacy of Sirna Nanoparticles Measured by Multimodality In Vivo Imaging”, Proceedings of the National Academy of Sciences, vol. 104, No.… [cited by applicant]
Bass, “Double-stranded RNA as a Template for Gene Silencing”, Cell, vol. 101, No. 3, 2000, 235-238. [cited by applicant]
Bawage, et al., “Synthetic mRNA Expressed Cas13a Mitigates RNA Virus Infections”, bioRxiv preprint doi: https://doi.org/10.1101/370460, Jul. 23, 2018, 9 pages. [cited by applicant]
Belhaj, et al., “Plant Genome Editing Made Easy: Targeted Mutagenesis in Model and Crop Plants Using the CRISPR/Cas System”, Plant Methods, vol. 9, No. 1, Oct. 11, 2013, 1-10. [cited by applicant]
Bender, et al., “Receptor-Targeted Nipah Virus Glycoproteins Improve Cell-Type Selective Gene Delivery and Reveal a Preference for Membrane-Proximal Cell Attachment”, PLoS Pathogens, vol. 12, No. 6, e1005641, 2016, 28 p… [cited by applicant]
Bennetzen, et al., “Codon Selection in Yeast”, Journal of Biological Chemistry, vol. 257, No. 6, Mar. 1982, 3026-3031. [cited by applicant]
Bernstein, et al., “Role for a Bidentate Ribonuclease in the Initiation Step of RNA Interference”, Nature, vol. 409, No. 6818, 2001, 363-366. [cited by applicant]
Betchen, et al., “Future and Current Surgical Therapies in Parkinson's Disease”, Current Opinion in Neurology, vol. 16, No. 4, 2003, 487-493. [cited by applicant]
Binley, et al., “Safety and Biodistribution of an Equine Infectious Anemai Virus-Based Gene Therapy, RetinoStat, for Age-Related Macular Degeneration”, Human Gene Therapy, vol. 23, Sep. 2012, 980-991. [cited by applicant]
Biswas, et al., “CRISPRTarget Bioinformatic Prediction and Analysis of CrRNA Targets”, RNA Biology, vol. 10, No. 5, May 2013, 817-827. [cited by applicant]
Boch, et al., “Breaking the Code of DNA Binding Specificity of TAL-type III Effectors”, Science, vol. 326, No. 5959, Dec. 11, 2009, 1509-1512. [cited by applicant]
Boshart, et al., “A Very Strong Enhancer Is Located Upstream of an Immediate Early Gene of Human Cytomegalovirus”, Cell, vol. 41, No. 2, Jun. 1985, 521-530. [cited by applicant]
Buch, et al., “A Genome-Wide Association Study Confirms PNPLA3 and Identifies TM6SF2 and MBOAT7 as Risk Loci for Alcohol-Related Cirrhosis”, Nature Genetics, vol. 47, No. 12, 2015, 1443-1448. [cited by applicant]
Buchholz, et al., “Surface-Engineered Viral Vectors for Selective and Cell Type-Specific Gene Delivery”, Trends in Biotechnology, vol. 33, No. 12, 2015, 777-790. [cited by applicant]
Buchschacher, et al., “Human Immunodeficiency Virus Vectors for Inducible Expression of Foreign Genes”, Journal of Virology, vol. 66, No. 5, 1992, 2731-2739. [cited by applicant]
Buckholz, et al., “Yeast Systems for the Commercial Production of Heterologous Proteins”, Bio/Technology, vol. 9, Nov. 1991, 1067-1072. [cited by applicant]
Byrne, et al., “Multiplex Gene Regulation: A Two-Tiered Approach to Transgene Regulation in Transgenic Mice”, Proceedings of the National Academy of Sciences, vol. 86, Jul. 1989, 5473-5477. [cited by applicant]
Calame, et al., “Transcriptional Controlling Elements in the Immunoglobulin and T Cell Receptor Loci”, Advances in Immunology, vol. 43, Feb. 1988, 235-275. [cited by applicant]
Campbell, “Codon Usage in Higher Plants, Green Algae, and Cyanobacteria”, Plant Physiology, vol. 92, No. 1, Jan. 1990, 1-11. [cited by applicant]
Camper, et al., “Postnatal Repression of the Alpha-Fetoprotein Gene is Enhancer Independent”, Genes and Development, vol. 3, 1989, 537-546. [cited by applicant]
Capone, et al., “Expression in Different Populations of Cells of the Root Meristem is Controlled by Different Domains of the roIB Promoter”, Plant Molecular Biology, vol. 25, 1994, 681-691. [cited by applicant]
Carr, et al., “Genome Engineering”, Nature Biotechnology, vol. 27, No. 12, Dec. 9, 2009, 1151-1162. [cited by applicant]
Casas, et al., “Transgenic Sorghum Plants via Microprojectile Bombardment”, Proceedings of the National Academy of Sciences, vol. 90, Dec. 1993, 11212-11216. [cited by applicant]
Chambers, et al., “Genome-wide Association Study Identifies Loci Influencing Concentrations of Liver Enzymes in Plasma”, Nature Genetics, vol. 43, No. 11, 2011, 1131-1138. [cited by applicant]
Chamoun-Emaneulli, et al., “In Vitro Incorporation of a Cell-Binding Protein to a Lentiviral Vector Using an Engineered Split Intein Enables Targeted Delivery of Genetic Cargo”, Biotechnology and Bioengineering, vol. 11… [cited by applicant]
Chang, et al., “Second-generation PLINK: Rising to the Challenge of Larger and Richer Datasets”, GigaScience, vol. 4, Article No. 7, 2015, 16 pages. [cited by applicant]
Chen, et al., “Dynamic Imaging of Genomic Loci in Living Human Cells by an Optimized CRISPR/Cas System”, Cell, vol. 155, Issue 7, Dec. 19, 2013, 1479-1491. [cited by applicant]
Cho, et al., “Lipid-like Nanoparticles for Small Interfering RNA Delivery to Endothelial Cells”, Advanced Functional Materials, vol. 19, Issue 19, Oct. 9, 2009, 15 pages. [cited by applicant]
Choi, et al., “Mechanism for the Endocytosis of Spherical Nucleic Acid Nanoparticle Conjugates”, Proceedings of the National Academy of Sciences, vol. 110, No. 19, 2013, 6 pages. [cited by applicant]
Chu, et al., “Efficient Generation of Rosa26 Knock-in Mice using Crispr/cas9 in C57bl/6 Zygotes”, BMC Biotechnology, vol. 16, No. 4, Jan. 16, 2016, 15 pages. [cited by applicant]
Cideciyan, et al., “Vision 1 Year after Gene Therapy for Leber's Congenital Amaurosis”, The New England Journal of Medicine, vol. 361, 2009, 725-727. [cited by applicant]
Cockrell, et al., “Gene Delivery by Lentivirus Vectors”, Molecular Biotechnology, vol. 36, 2007, 184-204. [cited by applicant]
Cooney, et al., “Hybrid Nonviral/Viral Vector Systems for Improved piggyBac DNA Transposon In Vivo Delivery”, Molecular Therapy, vol. 23, No. 4, 2015, 667-674. [cited by applicant]
Cox, et al., “RNA Editing with CRISPR-Cas13”, Science, vol. 358, No. 6366, Nov. 24, 2017, 23 pages. [cited by applicant]
Crane, et al., “Rescue Administration of a Helper-Dependent Adenovirus Vector with Long-Term Efficacy in Dogs with Glycogen Storage Disease Type Ia”, Gene Therapy, vol. 9, 2012, 443-452. [cited by applicant]
Cronican, et al., “A Class of Human Proteins That Deliver Functional Proteins Into Mammalian Cells In Vitro and In Vivo”, Chemistry & Biology, vol. 18, Issue 7, Jul. 29, 2011, 10 pages. [cited by applicant]
Cronican, et al., “Potent Delivery of Functional Proteins into Mammalian Cells in Vitro and in Vivo Using a Supercharged Protein”, ACS Chemical Biology, vol. 5, No. 8, 2010, 747-752. [cited by applicant]
Croyle, et al., “PEGylated Helper-Dependent Adenoviral Vectors: Highly Efficient Vectors with an Enhanced Safety Profile”, Gene Therapy, vol. 12, 2005, 579-587. [cited by applicant]
Cutler, et al., “Polyvalent Nucleic Acid Nanostructures”, Journal of the American Chemical Society, vol. 133, Issue 24, Jun. 22, 2011, 10 pages. [cited by applicant]
Cutler, et al., “Spherical Nucleic Acids”, Journal of the American Chemical Society, vol. 134, Issue 3, 2012, 1376-1391. [cited by applicant]
Dahlman, et al., “In Vivo Endothelial Sirna Delivery Using Polymeric Nanoparticles with Low Molecular Weight”, Nature Nanotechnology, vol. 9, No. 8, Aug. 2014, 17 pages. [cited by applicant]
Datsomor, et al., “CRISPR/Cas9-Mediated Ablation of ElovI2 in Atlantic Salmon ( [cited by applicant]
Davey, et al., “Direct DNA Transfer to Plant Cells”, Plant Molecular Biology, vol. 13, 1989, 273-285. [cited by applicant]
Davis, et al., “Evidence of RNAi in Humans From Systemically Administered siRNA via Targeted Nanoparticles”, Nature, vol. 464, No. 7291, Apr. 15, 2010, 1067-1070. [cited by applicant]
De Veylder, et al., “Herbicide Safener-Inducible Gene Expression in [cited by applicant]
Denny, et al., “PheWAS: Demonstrating the Feasibility of a Phenome-Wide Scan to Discover Gene-Disease Associations”, Bioinformatics, vol. 26, No. 9, 2010, 1205-1210. [cited by applicant]
Deshpande, et al., “Current Trends in the Use of Liposomes for Tumor Targeting”, Nanomedicine (Lond), vol. 8, No. 9, Sep. 2013, 32 pages. [cited by applicant]
Digiusto, et al., “RNA-Based Gene Therapy for HIV with Lentiviral Vector-Modified CD34(+) Cells in Patients Undergoing Transplantation for AIDSrelated Lymphoma”, Science Translational Medicine, vol. 2, Issue 36, Jun. 16… [cited by applicant]
Do, et al., “Exome Sequencing Identifies Rare LDLR and APOA5 Alleles Conferring Risk for Myocardial Infarction”, Nature, vol. 518, No. 7537, 2015, 102-106. [cited by applicant]
Doyon, et al., “Enhancing Zinc-Finger-Nuclease Activity With Improved Obligate Heterodimeric Architectures”, Nature Methods, vol. 8, No. 1, Jan. 2011, 74-79. [cited by applicant]
Duan, “CRISPR Alleviates Muscular Dystrophy in Dogs”, Nature Biomedical Engineering, vol. 2, 2018, 795-796. [cited by applicant]
Durr, et al., “Carcinogenesis of Primary Liver Malignancies”, Langenbeck's Archives of Surgery, vol. 385, No. 3, 2000, 154-161. [cited by applicant]
Edlund, et al., “Cell-Specific Expression of the Rat Insulin Gene: Evidence for Role of Two Distinct 5∝ Flanking Elements”, Science. vol. 230, No. 4728, Nov. 22, 1985, 912-916. [cited by applicant]
Ehrhardt, et al., “Somatic Integration From an Adenoviral Hybrid Vector Into a Hot Spot in Mouse Liver Results in Persistent Transgene Expression Levels in Vivo”, Molecular Therapy, vol. 15, No. 1, 2007, 146-156. [cited by applicant]
El-Andaloussi, et al., “Exosome-Mediated Delivery of siRNA in Vitro and in Vivo”, Nature Protocols, vol. 7, Issue 12, Dec. 2012, 2112-2126. [cited by applicant]
Elbashir, et al., “Duplexes of 21-nucleotide RNAs Mediate RNA Interference in Cultured Mammalian Cells”, Nature, vol. 411, No. 6836, 2001, 494-498. [cited by applicant]
Elbashir, et al., “Functional Anatomy of siRNAs for Mediating Efficient RNAi in [cited by applicant]
Elbashir, et al., “RNA Interference Is Mediated by 21- And 22-nucleotide RNAs”, Genes Development, vol. 15, No. 2, 2001, 188-200. [cited by applicant]
Elmen, et al., “Locked Nucleic Acid (LNA) Mediated Improvements in siRNA Stability and Functionality”, Nucleic Acids Research, vol. 33, Issue 1, Jan. 2005, 439-447. [cited by applicant]
Emdin, et al., “Analysis of Predicted Loss-Of-Function Variants in UK Biobank Identifies Variants Protective for Disease”, Nature Communications vol. 9, Article No. 1613, 2018, 8 pages. [cited by applicant]
Emdin, et al., “Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling”, Circulation, vol. 137, No. 3, Jan. 16, 2018, 222-232. [cited by applicant]
Enkirch, et al., “Targeted Lentiviral Vectors Pseudotyped With The Tupaia Paramyxovirus Glycoproteins”, Gene Therapy vol. 20, 2013, 16-23. [cited by applicant]
Esvelt, et al., “Orthogonal Cas9 Proteins for RNA-guided Gene Regulation and Editing”, Nature Methods, vol. 10, No. 11, Nov. 2013, 19 pages. [cited by applicant]
Fire, et al., “Potent and Specific Genetic Interference by Double-Stranded Rna in Caenorhabditis Elegans”, Nature, vol. 391, No. 6669, Feb. 1998, 806-811. [cited by applicant]
Flotte, et al., “A Phase I Study of an Adeno-Associated virus-CFTR Gene Vector in Adult CF Patients With Mild Lung Disease”, Human Gene Therapy, vol. 7, No. 9, 1996, 1145-1159. [cited by applicant]
Friedrich, et al., “DARPin-targeting of Measles Virus: Unique Bispecificity, Effective Oncolysis, and Enhanced Safety”, Molecular Therapy, vol. 21, No. 4, 2013, 849-859. [cited by applicant]
Fu, et al., “Linear Transgene Constructs Lacking Vector Backbone Sequences Generate Low-Copy-Number Transgenic Plants with Simple Integration Patterns”, Transgenic Research, Kluwer Academic Publishers, vol. 9, No. 1, 20… [cited by applicant]
Fuchsberger, et al., “The Genetic Architecture of Type 2 Diabetes”, Nature, vol. 536, Aug. 4, 2016, 29 pages. [cited by applicant]
Funke, et al., “Targeted Cell Entry of Lentiviral Vectors”, Molecular Therapy vol. 16 No. 8, 2008, 1427-1436. [cited by applicant]
Gallie, “Introduction of mRNA to Plant Protoplasts using Polyethylene Glycol”, Plant Cell Reports, vol. 13, 1993, 119-122. [cited by applicant]
Gantz, et al., “Gene Editing Technologies and Applications for Insects”, Current Opinion in Insect Science, vol. 28, Aug. 2018, 66-72. [cited by applicant]
Gao, et al., “Engineered Cpf1 Enzymes with Altered PAM Specificities”, Nature Biotechnology, vol. 35, No. 8, Dec. 4, 2016, 17 pages. [cited by applicant]
Gatz, et al., “Regulation of a Modified CaMV 35S Promoter by the Tn10-Encoded Tet Repressor in Transgenic Tobacco”, Molecular Genetics and Genomics, vol. 227, No. 2, 1991, 229-237. [cited by applicant]
Gaudelli, et al., “Programmable Base Editing of A⋅T to G⋅C in Genomic DNA without DNA Cleavage”, Nature, vol. 551, No. 7681, Nov. 23, 2017, 37 pages. [cited by applicant]
Girard-Gagnepain, et al., “Baboon Envelope Pseudotyped LVs Outperform VSV-G-LVs for Gene Transfer Into Early-Cytokine-Stimulated And Resting HSCs”, Blood, vol. 124 No. 8, Aug. 21, 2014, 1221-1231. [cited by applicant]
Gleditzsch, et al., “PAM Identification by CRISPR-Cas Effector Complexes: Diversified Mechanisms and Structures”, RNA Biology, vol. 16. No. 4, 2019, 504-517. [cited by applicant]
Gorad, et al., “Liver Specific Drug Targeting Strategies: A Review”, International Journal of Pharmaceutical Sciences and Research, vol. 4, No. 11, 2013, 4145-4157. [cited by applicant]
Grissa, et al., “CRISPRFinder: A Web Tool to Identify Clustered Regularly Interspaced Short Palindromic Repeats”, Nucleic Acids Research, vol. 35, 2007, W52-W57. [cited by applicant]
Gruber, et al., “The Vienna RNA Websuite”, Nucleic Acids Research, vol. 36, Apr. 19, 2008, W70-W74. [cited by applicant]
Gruenewald, et al., “The Fourth Molybdenum Containing Enzyme mARC: Cloning and Involvement in the Activation of N-hydroxylated Prodrugs”, Journal of Medicinal Chemistry, vol. 51, No. 24, 2008, 8173-8177. [cited by applicant]
Grunweller, et al., “Comparison of Different Antisense Strategies in Mammalian Cells Using Locked Nucleic Acids, 2′-O-methyl RNA, Phosphorothioates and Small Interfering RNA”, Nucleic Acids Research, vol. 31, No. 12, 20… [cited by applicant]
Gui, et al., “CRISPR/Cas9-Mediated Genome Editing and Mutagenesis of EcChi4 in Exopalaemon carinicauda”, Genes Genomes Genetics (Bethesda), vol. 6, No. 11, Nov. 2016, 3757-3764. [cited by applicant]
Hall, et al., “Establishment and Maintenance of a Heterochromatin Domain”, Science, vol. 297, No. 5590, 2002, 2232-2237. [cited by applicant]
Hall, et al., “Genome Editing in Mice Using CRISPR/Cas9 Technology”, Current Protocols in Cell Biology, vol. 81, No. 1, 2018, 31 pages. [cited by applicant]
Hamilton, et al., “A Species of Small Antisense RNA in Posttranscriptional Gene Silencing in Plants”, Science, vol. 286, No. 5441, 1999, 950-952. [cited by applicant]
Hanawa, et al., “Comparison of Various Envelope Proteins for Their Ability to Pseudotype Lentiviral Vectors and Transduce Primitive Hematopoietic Cells From Human Blood”, Molecular Therapy, vol. 5, No. 3., Mar. 2002, 24… [cited by applicant]
Hao, et al., “Nucleic Acid-Gold Nanoparticle Conjugates as Mimics of microRNA”, Small, vol. 7, Issue 22, Nov. 18, 2011, 10 pages. [cited by applicant]
Hardee, et al., “Advances in Non-Viral DNA Vectors for Gene Therapy”, Genes , vol. 8, No. 2, 2017, 22 pages. [cited by applicant]
Harrison, et al., “A CRISPR View of Development”, Genes & Development, vol. 28, Sep. 1, 2014, 1859-1872. [cited by applicant]
Havemeyer, et al., “Identification of the Missing Component in the Mitochondrial Benzamidoxime Prodrug-Converting System as a Novel Molybdenum Enzyme”, Journal of Biological Chemistry, vol. 281, No. 46, Nov. 17, 2006, 3… [cited by applicant]
Heo, et al., “CRISPR/Cas9 Nuclease-Mediated Gene Knock-In in Bovine-Induced Pluripotent Cells”, Stem Cells Development, vol. 24, No. 3, Feb. 2015, 10 pages. [cited by applicant]
Hermonat, et al., “Use of Adeno-Associated Virus as a Mammalian DNA Cloning Vector: Transduction of Neomycin Resistance into Mammalian Tissue Culture Cells”, Proceedings of National Academy of Sciences, vol. 81, Oct. 19… [cited by applicant]
Hirel, et al., “Forcing Expression of a Soybean Root Glutamine Synthetase Gene in Tobacco Leaves Induces a Native Gene Encoding Cytosolic Enzyme”, Plant Molecular Biology, vol. 20, 1992, 207-218. [cited by applicant]
Hutvagner, et al., “A Cellular Function for the RNA-interference Enzyme Dicer in the Maturation of the let-7 Small Temporal RNA”, Science, vol. 293, No. 5531, 2001, 834-838. [cited by applicant]
Hutvagner, et al., “A MicroRNA in a Multiple-Turnover RNAi Enzyme Complex”, Science, vol. 297, 5589, Oct. 2002, 2056-2060. [cited by applicant]
Ivics, et al., “Molecular Reconstruction of Sleeping Beauty, a Tc1-like Transposon From Fish, and Its Transposition in Human Cells”, Cell, vol. 91, No. 4, Nov. 14, 1997, 501-510. [cited by applicant]
Jensen, et al., “Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma”, Science Translational Medicine, vol. 5, Issue 209, Oct. 30, 2013, 12 pages. [cited by applicant]
Jensen, et al., “Unlocked Nucleic Acid (UNA) and UNA Derivatives: Thermal Denaturation Studies”, Nucleic Acids Symposium Series, vol. 52, Issue No. 1, 2008, 133-134. [cited by applicant]
Jenuwein, “An RNA-Guided Pathway for the Epigenome”, Science, vol. 297, Issue 5590, 2002, 2215-2218. [cited by applicant]
Ji, et al., “Genome-wide Association Study of Primary Sclerosing Cholangitis Identifies New Risk Loci and Quantifies the Genetic Relationship With Inflammatory Bowel Disease”, Nature Genetics, vol. 49, No. 2, Feb. 2017,… [cited by applicant]
Jiang, et al., “RNA-Guided Editing of Bacterial Genomes Using CRISPR-Cas Systems”, Nature Biotechnology, vol. 31, No. 3, Mar. 2013, 233-239. [cited by applicant]
Jin, et al., “Safe Engineering of CAR T Cells for Adoptive Cell Therapy of Cancer Using Long-term Episomal Gene Transfer”, EMBO Molecular Medicine, vol. 8, No. 7, 2016, 702-711. [cited by applicant]
Johann, et al., “GLVR1, a Receptor for Gibbon Ape Leukemia Virus, is Homologous to a Phosphaate Permease of Neurospora crassa and is Expresssed at High Levels in the Brain and Thymus”, Journal of Virology, vol. 66, No. … [cited by applicant]
Kabadi, et al., “Multiplex CRISPR/Cas9-based Genome Engineering from a Single Lenttiviral Vector”, Nucleic Acids Research, vol. 42, No. 19, Aug. 13, 2014, 11 pages. [cited by applicant]
Kalds, et al., “Sheep and Goat Genome Engineering: From Random Transgenesis to the CRISPR Era”, Frontiers in Genetics, vol. 10, Article 750, Sep. 2019, 27 pages. [cited by applicant]
Kalimuthu, et al., “Human Mitochondrial Amidoxime Reducing Component (mARC): An Electrochemical Method for Identifying New Substrates and Inhibitors”, Electrochemistry Communications, vol. 84, Nov. 2017, 90-93. [cited by applicant]
Kanai, et al., “Genetic Analysis of Quantitative Traits in the Japanese Population Links Cell Types to Complex Human Diseases”, Nature, vol. 50, 2018, 390-400. [cited by applicant]
Karimi-Ashtiyani, et al., “Point Mutation Impairs Centromeric CENH3 Loading and Induces Haploid Plants”, Proceedings of the National Academy of Sciences, vol. 112, No. 36, Sep. 8, 2015, 11211-11216. [cited by applicant]
Kasaraneni, et al., “A Simple Strategy for Retargeting Lentiviral Vectors to Desired Cell Types via a Disulfide-Bond-Forming Protein-Peptide Pair”, Scientific Reports, vol. 8, No. 10990, 2018, 9 pages. [cited by applicant]
Kaufman, et al., “Translational Efficiency of Polycistronic MRNAs and their Utilization to Express Heterologous Genes in Mammalian Cells”, The EMBO Journal, vol. 6, No. 1, 1987, 187-195. [cited by applicant]
Kawai, et al., “Transformation of [cited by applicant]
Kawamata, et al., “Temporal and Spatial Pattern of Expression of the Pea Phenylalanine Ammonia-Lyase Gene1 Promoter in Transgenic Tobacco”, Plant Cell Physiology, vol. 38, No. 7, 1997, 792-803. [cited by applicant]
Kay, et al., “Evidence for Gene Transfer and Expression of Factor IX in Haemophilia B Patients Treated With an AAV Vector”, Nature Genetics, vol. 24, No. 3, 2000, 257-261. [cited by applicant]
Kessel, et al., “Murine Developmental Control Genes”, Science, vol. 249, No. 4967, Jul. 27, 1990, 374-379. [cited by applicant]
Khera, et al., “Association of Rare and Common Variation in the Lipoprotein Lipase Gene with Coronary Artery Disease”, The Journal of the American Medical Association, vol. 317, No. 9, Mar. 7, 2017, 937-946. [cited by applicant]
Khera, et al., “Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia”, Journal of the American College of Cardiology, vol. 67, No. 22, 2016… [cited by applicant]
Kim, et al., “Chimeric Restriction Endonuclease”, Proceedings of the National Academy of Sciences, vol. 91, No. 3, 1994, 883-887. [cited by applicant]
Kim, et al., “Highly Efficient Rna-guided Genome Editing in Human Cells via Delivery of Purified Cas9 Ribonucleoproteins”, Genome Research, vol. 24, No. 6, Jun. 24, 2014, 1012-1019. [cited by applicant]
Kim, et al., “Hybrid Restriction Enzymes: Zinc Finger Fusions to Fok I Cleavage Domain”, Proceedings of the National Academy of Sciences, vol. 93 No. 3, Feb. 1996, 1156-1160. [cited by applicant]
Klein, et al., “High-velocity Microprojectiles for Delivering Nucleic Acids into Living Cells”, Nature, vol. 327, 1987, 70-73. [cited by applicant]
Klein, et al., “The Mitochondrial Amidoxime-reducing Component (mARC1) Is a Novel Signal-anchored Protein of the Outer Mitochondrial Membrane”, Journal of Biological Chemistry, vol. 287, 2012, 42795-42803. [cited by applicant]
Klein, et al., “Transformation of Microbes, Plants and Animals by Particle Bombardment”, Bio/Technology, vol. 10, 1992, 286-291. [cited by applicant]
Kleinstiver, et al., “Engineered Crispr-Cas9 Nucleases with Altered Pam Specificities”, Nature, vol. 523, No. 7561, Jul. 23, 2015, 17 pages. [cited by applicant]
Klompe, et al., “Transposon-encoded CRISPR-Cas Systems Direct RNA-guided DNA Integration”, Nature, vol. 571, Jul. 11, 2019, 24 pages. [cited by applicant]
Komor, et al., “Programmable Editing of a Target Base in Genomic DNA without Double-Stranded DNA Cleavage”, Nature, vol. 533, No. 7603, May 19, 2016, 17 pages. [cited by applicant]
Koonin, et al., “Origins and Evolution of CRISPR-Cas Systems”, Philosophical Transactions of the Royal Society of London, vol. 374, Issue 1772, Oct. 24, 2018, 16 pages. [cited by applicant]
Kotin, “Prospects for the Use of Adeno-Associated Virus as a Vector for Human Gene Therapy”, Human Gene Therapy, vol. 5, 1994, 793-801. [cited by applicant]
Kotthaus, et al., “Reduction of Nω-Hydroxy-L-Arginine by the Mitochondrial Amidoxime Reducing Component (mARC)”, Biochemical Journal, vol. 433, Issue 2, Jan. 2011, 383-391. [cited by applicant]
Kotwica-Rolinska, “CRISPR/Cas9 Genome Editing Introduction and Optimization in the Non-model Insect [cited by applicant]
Kozlitina, et al., “Exome-wide Association Study Identifies a TM6SF2 Variant That Confers Susceptibility to Nonalcoholic Fatty Liver Disease”, Nature Genetics, vol. 46, No. 4, 2014, 352-356. [cited by applicant]
Kubitza, et al., “Crystal Structure of Human mARC1 Reveals Its Exceptional Position Among Eukaryotic Molybdenum Enzymes”, Proceedings of the National Academy of Sciences, vol. 115, No. 47, Nov. 20, 2018, 11958-11963. [cited by applicant]
Kubo, et al., “A New Hybrid System Capable of Efficient Lentiviral Vector Production and Stable Gene Transfer Mediated by a Single Helper-Dependent Adenoviral Vector”, Journal of Virology, vol. 77, No. 5, Mar. 2003, 296… [cited by applicant]
Kubo, et al., “Adenovirus—Retrovirus Hybrid Vectors Achieve Highly Enhanced Tumor Transduction and Antitumor Efficacy In Vivo”, Molecular Therapy, vol. 19, No. 1, 2011, 76-82. [cited by applicant]
Kurjan, et al., “Structure of A Yeast Pheromone Gene (Mfα): A Putative A-Factor Precursor Contains Four Tandem Copies of Mature A-Factor”, Cell, vol. 30, No. 3, Nov. 1982, 933-943. [cited by applicant]
Kuster, et al., “The Promoter of the [cited by applicant]
Lagauzère, “Viromer® RED, a powerful tool for transfection of keratinocytes”, doi: 10.13140/RG.2.2.16993.61281, Aug. 2017, 6 pages. [cited by applicant]
Lagauzère, “Viromer® Transfection—Factbook 2018: Technology, Product Overview, Users' Data”, Project: Viromer®: an innovative technology for transfection DOI: 10.13140/RG.2.2.23912.16642, 2018, 21 pages. [cited by applicant]
Lai, et al., “Adenovirus and Adeno-Associated Virus Vectors”, DNA Cell Biology. vol. 21, No. 12, 2002, 895-913. [cited by applicant]
Lawrence, et al., “Supercharging Proteins Can Impart Unusual Resilience”, Journal of the American Chemical Society, vol. 129, Issue 33, Aug. 1, 2007, 8 pages. [cited by applicant]
Lee, et al., “Engraftment of Human iPS Cells and Allogenic Porcine Cells into Pigs with Inactivated RAG2 and Acompanying Severe Combined Immunodeficiency”, Proceedings of the National Academy of Sciences, vol. 111, No. … [cited by applicant]
Li, et al., “Base Editing With a Cpf1-cytidine Deaminase Fusion”, Nature Biotechnology, vol. 36, 2018, 324-327. [cited by applicant]
Li, et al., “piggyBac Transposase Tools for Genome Engineering”, Proceedings of the National Academy of Sciences, vol. 110, No. 25, Jun. 18, 2013, E2279-E2287. [cited by applicant]
Li, et al., “Protein Transport into Chloroplasts”, Annual Review of Plant Biology, vol. 61, 2010, 157-180. [cited by applicant]
Liang, et al., “CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes”, Protein Cell 2015, vol. 6, No. 5, Accepted Apr. 1, 2015, pp. 363-372. [cited by applicant]
Lima, et al., “Single-stranded siRNAs Activate RNAi in Animals”, Cell, vol. 150, No. 3, 2012, 883-894. [cited by applicant]
Lin, et al., “Policing Rogue Genes”, Nature, vol. 402, 1999, 128-129. [cited by applicant]
Liu, et al., “Exome-wide Association Study of Plasma Lipids in >300,000 Individuals”, Nature Genetics, vol. 49, No. 12, Dec. 2017, 1758-1766. [cited by applicant]
Liu, et al., “Expanding the CRISPR Toolbox in Zebrafish for Studying Development and Disease”, Frontiers in Cell and Developmental Biology, vol. 7, Article 13, Mar. 2019, 15 pages. [cited by applicant]
Liu, et al., “Highly Efficient RNA-Guided Base Editing in Rabbit”, Nature Communications, vol. 9, Article No. 2717, 2018, 10 pages. [cited by applicant]
Liu, et al., “Multiple Homologous Genes Knockout (KO) by CRISPR/Cas9 System in Rabbit”, Gene, vol. 647, Mar. 2018, 261-267. [cited by applicant]
Liu, et al., “Recombinant Human Foamy Virus, a Novel Vector for Neurological Disorders Gene Therapy, Drives Production of GAD in Cultured Astrocytes”, Molecular Therapy, vol. 15, No. 10, 2007, 1834-1841. [cited by applicant]
Liu, et al., “The Effect of the TM6SF2 E167K Variant on Liver Steatosis and Fibrosis in Patients with Chronic Hepatitis C: A Meta-Analysis”, Scientific Reports, vol. 7, Article No. 9273, 2017, 11 pages. [cited by applicant]
Liu, et al., “TM6SF2 rs58542926 Influences Hepatic Fibrosis Progression in Patients with Non-Alcoholic Fatty Liver Disease”, Nature Communications, vol. 5, Article No. 4309, 2014, 6 pages. [cited by applicant]
Locke, et al., “Genetic Studies of Body Mass Index Yield New Insights for Obesity Biology”, Nature, vol. 518, Feb. 2015, 197-206. [cited by applicant]
Lok, “CRISPR/Cas9 Mutagenesis and Expression of Dominant Mutant Transgenes as Functional Genomic Approaches in Parasitic Nematodes”, Frontiers in Genetics, vol. 10, Article 656, Jul. 2019, 11 pages. [cited by applicant]
Lorenzer, et al., “Going Beyond the Liver: Progress and Challenges of Targeted Delivery of siRNA Therapeutics”, Journal of Controlled Release, vol. 203, Apr. 2015, 1-15. [cited by applicant]
Lowder, et al., “A CRISPR/Cas9 Toolbox for Multiplexed Plant Genome Editing and Transcriptional Regulation”, Plant Physiology, vol. 169, No. 2, Oct. 2015, 15 pages. [cited by applicant]
Lozano, et al., “Global and Regional Mortality From 235 Causes of Death for 20 Age Groups in 1990 and 2010: A Systematic Analysis for the Global Burden of Disease Study 2010”, The Lancet, vol. 380, No. 9859, Dec. 2012, … [cited by applicant]
Luckow, et al., “High Level Expression of Nonfused Foreign Genes with Autographa Californica Nuclear Polyhedrosis Virus Expression Vectors”, Virology, vol. 170, Issue 1, May 1989, 31-39. [cited by applicant]
Ma, et al., “A Robust CRISPR/Cas9 System for Convenient High-Efficiency Multiplex Genome Editing in Monocot and Dicot Plants”, Molecular Plant, vol. 8, Aug. 2015, 1274-1284. [cited by applicant]
Macparland, et al., “Single Cell RNA Sequencing of Human Liver Reveals Distinct Intrahepatic Macrophage Populations”, Nature Communications, vol. 9, Article No. 4383, 2018, 21 pages. [cited by applicant]
Makarova, et al., “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?”, The CRISPR Journal, vol. 1, No. 5, 2018, 325-336. [cited by applicant]