IP Library › Granted Patent US 12,186,409
Granted Patent B2
US 12,186,409 · App. 17/088,237 · Granted Jan 7, 2025

Methods of screening for sortilin binding antagonists

Inventors: Arnon Rosenthal (Woodside, CA); Tina Schwabe (San Francisco, CA)
Assignee: ALECTOR LLC
A61K49/0056C07K16/2863G01N21/6428G01N33/533G01N33/542G01N2333/705G01N2500/02G01N2500/10
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 12,186,409
App. No.
17/088,237
Granted
Jan 7, 2025
Kind
B2
Abstract

The present disclosure provides methods of screening for a sortilin binding antagonist. In some embodiments, the methods include incubating an agent with a sortilin protein and a sortilin ligand, where the sortilin protein and sortilin ligand are each attached to a member of a fluorescence donor/acceptor pair, exciting the fluorescence donor of the fluorescence donor/acceptor pair, and detecting fluorescence emitted by the fluorescence donor at a second wavelength and fluorescence emitted by the fluorescence acceptor at a third wavelength. A decrease in the ratio of the fluorescence emitted by the fluorescence acceptor at the third wavelength to the fluorescence emitted by the fluorescence donor at the second wavelength, as compared to the ratio in the absence of the agent, indicates that the agent is a sortilin binding antagonist.

Claims (23)

1. A method of screening for a sortilin binding antagonist, comprising:

(a) contacting a cell expressing a sortilin protein on its cell surface with an agent and a sortilin ligand under conditions in which the sortilin protein is capable of binding to the sortilin ligand,

wherein the sortilin ligand is attached to a fluorescent detection donor moiety and wherein the fluorescent detection donor moiety is Terbium cryptate;

wherein the sortilin protein is attached to a fluorescent detection acceptor moiety and wherein the fluorescent detection acceptor moiety is d2;

(b) exciting the sortilin ligand attached to Terbium cryptate with light of a first wavelength sufficient for fluorescence resonance energy transfer (FRET) to occur between the Terbium cryptate and the d2; and p 1 (c) detecting fluorescence emitted by the Terbium cryptate at a second wavelength and fluorescence emitted by the d 2 at a third wavelength; wherein

(i) d2 is directly coupled to the sortilin protein, and Terbium cryptate is coupled to Streptavidin, which is bound to biotin coupled to the sortilin ligand; or

(ii) d2 is coupled to an antibody that specifically binds to the sortilin protein, and Terbium cryptate is coupled to streptavidin, which is bound to biotin coupled to the sortilin ligand; and

wherein a decrease in the ratio of the fluorescence emitted by the d2 at the third wavelength to the fluorescence emitted by the Terbium cryptate at the second wavelength, as compared to the ratio in the absence of the agent, indicates that the agent is a sortilin binding antagonist.

2. The method of claim 1 , wherein said sortilin ligand is a progranulin (PGRN) protein.

3. The method of claim 2 , wherein said PGRN protein comprises the amino acid sequence of SEQ ID NO:3.

4. The method of claim 2 , wherein said PGRN protein comprises the amino acid sequence of SEQ ID NO:4.

5. The method of claim 1 , wherein the sortilin ligand is selected from the group consisting of a neurotensin protein, a pro-sortilin peptide, a spadin peptide, a pro-nerve growth factor (pro-NGF protein), a proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, or an amyloid precursor protein (APP) protein.

6. The method of claim 1 , wherein the cell expressing a sortilin protein on its cell surface is a mammalian cell.

7. The method of claim 6 , wherein the mammalian cell is selected from the group consisting of a monkey kidney CV1 cell transformed by SV40, a human embryonic kidney cell, a HEK-293 cell, a HEK-293T cell, a baby hamster kidney cell, a mouse sertoli cell, a monkey kidney cell, an African green monkey kidney cell, a human cervical carcinoma cell, a canine kidney cell, a buffalo rat liver cell, a human lung cell, a human liver cell, a mouse mammary tumor cell, a TRI cell, a Chinese hamster ovary cell, and a myeloma cell.

8. The method of claim 6 , wherein the mammalian cell is a human embryonic kidney cell.

9. The method of claim 1 , wherein the cell expressing a sortilin protein on its cell surface is viable over the timescale of the method.

10. The method of claim 1 , wherein the cell expressing a sortilin protein on its cell surface is cultured in a cell culture medium containing the sortilin ligand.

11. The method of claim 1 , wherein the agent is a small molecule, wherein the small molecule has molecular mass that is <1,000 Da, or a protein.

12. The method of claim 11 , wherein the protein is an antibody that binds to sortilin.

13. The method of claim 1 , wherein the failure of decrease in the level of the sortilin ligand is detected by a plate reader, a flow cytometer, or fluorescence microscopy.

14. The method of claim 1 , wherein the first wavelength is about 337 nm.

15. The method of claim 1 , wherein the second wavelength is about 620 nm.

16. The method of claim 1 , wherein the third wavelength is about 665 nm.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 4, 2020
From: ROSENTHAL, ARNON; SCHWABE, TINA
To: ALECTOR LLC
Reel/Frame 054274/0044 →
Continuity (3)
Division 15565063
Provisional Application 62144277 · Apr 7, 2015
Related Publication 20210121583A1 · Apr 29, 2021
References Cited (157)
US RE30985E · Cartaya · 1982 [cited by applicant]
US 4560655A · Baker · 1985 [cited by applicant]
US 4657866A · Kumar · 1987 [cited by applicant]
US 4767704A · Cleveland et al. · 1988 [cited by applicant]
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 4927762A · Darfler · 1990 [cited by applicant]
US 5122469A · Mather et al. · 1992 [cited by applicant]
US 5545806A · Lonberg et al. · 1996 [cited by applicant]
US 5545807A · Surani et al. · 1996 [cited by applicant]
US 5569825A · Lonberg et al. · 1996 [cited by applicant]
US 5625126A · Lonberg et al. · 1997 [cited by applicant]
US 5633425A · Lonberg et al. · 1997 [cited by applicant]
US 5661016A · Lonberg et al. · 1997 [cited by applicant]
US 8008009B2 · Choquet-Kastylevsky et al. · 2011 [cited by applicant]
US 8066997B2 · Nykjaer et al. · 2011 [cited by applicant]
US 8460657B2 · Nykjaer et al. · 2013 [cited by applicant]
US 8703125B2 · Pedersen et al. · 2014 [cited by applicant]
US 8748384B2 · Andersen et al. · 2014 [cited by applicant]
US 8795627B2 · Starr et al. · 2014 [cited by applicant]
US 8815808B2 · Nykjaer et al. · 2014 [cited by applicant]
US 8877714B2 · Starr et al. · 2014 [cited by applicant]
US 8986690B2 · Nykjaer et al. · 2015 [cited by applicant]
US 9061045B2 · Choquet-Kastylevsky et al. · 2015 [cited by applicant]
US 9062126B2 · Zankel et al. · 2015 [cited by applicant]
US 9084745B2 · Nykjaer et al. · 2015 [cited by applicant]
US 9234036B2 · Anderson et al. · 2016 [cited by applicant]
US 9605073B2 · Nykjaer et al. · 2017 [cited by applicant]
US 9670263B2 · Pedersen et al. · 2017 [cited by applicant]
US 9822366B2 · Aikawa et al. · 2017 [cited by applicant]
US 10221438B2 · Gosselin · 2019 [cited by examiner]
US 10849992B1 · Rosenthal et al. · 2020 [cited by applicant]
US 20030003444A1 · Pelletier et al. · 2003 [cited by applicant]
US 20050096516A1 · Soykan et al. · 2005 [cited by applicant]
US 20080213270A1 · Piliponsky et al. · 2008 [cited by applicant]
US 20090068200A1 · Choquet-Kastylevsky et al. · 2009 [cited by applicant]
US 20090220988A1 · Trinquet · 2009 [cited by applicant]
US 20100028333A1 · Getty et al. · 2010 [cited by applicant]
US 20100105034A1 · Hutton et al. · 2010 [cited by applicant]
US 20110104666A1 · Matsubara et al. · 2011 [cited by applicant]
US 20110166036A1 · Nykjaer et al. · 2011 [cited by applicant]
US 20120039865A1 · Strittmatter et al. · 2012 [cited by applicant]
US 20120315244A1 · Yuan et al. · 2012 [cited by applicant]
US 20130115222A1 · Hempstead et al. · 2013 [cited by applicant]
US 20130171173A1 · Choquet-Kastylevsky et al. · 2013 [cited by applicant]
US 20130336988A1 · Hempstead et al. · 2013 [cited by applicant]
US 20140004108A1 · Yuan et al. · 2014 [cited by applicant]
US 20140038942A1 · Karstens · 2014 [cited by examiner]
US 20150299304A1 · Nykjaer et al. · 2015 [cited by applicant]
US 20150368231A1 · Maltas et al. · 2015 [cited by applicant]
US 20160024172A1 · Zankel et al. · 2016 [cited by applicant]
US 20160060346A1 · Andersen et al. · 2016 [cited by applicant]
US 20160159871A1 · Zecri · 2016 [cited by examiner]
US 20160194631A1 · Yuan et al. · 2016 [cited by applicant]
US 20160349276A1 · Jepsen et al. · 2016 [cited by applicant]
US 20170049855A1 · Liu et al. · 2017 [cited by applicant]
US 20170096486A1 · Landberg · 2017 [cited by applicant]
US 20170158766A1 · Nykjaer et al. · 2017 [cited by applicant]
US 20170210808A1 · Rosenthal et al. · 2017 [cited by applicant]
US 20170240611A1 · Pedersen et al. · 2017 [cited by applicant]
US 20170246263A1 · Concino et al. · 2017 [cited by applicant]
US 20170247391A1 · Grembecka et al. · 2017 [cited by applicant]
US 20170267761A1 · Biilmann Ronn et al. · 2017 [cited by applicant]
US 20170318057A1 · Nykjaer et al. · 2017 [cited by applicant]
WO WO1987000195A1 · 1987 [cited by applicant]
WO WO1987004462A1 · 1987 [cited by applicant]
WO WO1990003430A1 · 1990 [cited by applicant]
WO WO1991010741A1 · 1991 [cited by applicant]
WO WO1996033735A1 · 1996 [cited by applicant]
WO WO1996034096A1 · 1996 [cited by applicant]
WO WO1998024893A1 · 1998 [cited by applicant]
WO WO2004056385A2 · 2004 [cited by applicant]
WO WO2005044293A2 · 2005 [cited by applicant]
WO WO2006138343A2 · 2006 [cited by applicant]
WO WO2007035716A2 · 2007 [cited by applicant]
WO WO2007088305A1 · 2007 [cited by applicant]
WO WO2008036682A2 · 2008 [cited by applicant]
WO WO2008052016A2 · 2008 [cited by applicant]
WO WO2008074329A2 · 2008 [cited by applicant]
WO WO2008076262A2 · 2008 [cited by applicant]
WO WO2008086452A2 · 2008 [cited by applicant]
WO WO2009140972A2 · 2009 [cited by applicant]
WO WO2009155932A2 · 2009 [cited by applicant]
WO WO2010022175A1 · 2010 [cited by applicant]
WO WO2010028333A2 · 2010 [cited by applicant]
WO WO2010069331A2 · 2010 [cited by applicant]
WO WO2011041582A2 · 2011 [cited by applicant]
WO WO2011159762A1 · 2011 [cited by applicant]
WO WO2012068332A2 · 2012 [cited by applicant]
WO WO2014071131A1 · 2014 [cited by applicant]
WO WO2015119989A1 · 2015 [cited by applicant]
WO WO2015121166A1 · 2015 [cited by applicant]
WO WO2015144860A1 · 2015 [cited by applicant]
WO WO2016025523A1 · 2016 [cited by applicant]
WO WO2016164608A1 · 2016 [cited by applicant]
WO WO2016164637A1 · 2016 [cited by applicant]
WO WO2017009327A1 · 2017 [cited by applicant]
WO WO2017024137A1 · 2017 [cited by applicant]
Xu et al., A bioluminescence resonance energy transfer (BRET) system: Application to interacting circadian clock proteins, Proc. Natl. Acad. Sci, vol. 96, 1999, pp. 151-156. (Year: 1999). [cited by examiner]
Diamandis et al., Immunoassay, Academic Press, Chapter 11, The Avidin-Biotin System, pp. 237-267, 1996. (Year: 1996). [cited by examiner]
Andersen et al., “Identification of the First Small-Molecule Ligand of the Neuronal Receptor Sortilin and Structure Determination of the Receptor-Ligand Complex”, Acta Crystallographica Section D Biological Crystallogra… [cited by applicant]
Baker et al., “Mutations in Progranulin Cause Tau-Negative Frontotemporal Dementia Linked to Chromosome 17”, Nature, vol. 442, Aug. 24, 2006, pp. 916-919. [cited by applicant]
Barnes et al., “Methods for Growth of Cultured Cells in Serum-Free Medium”, Analytical Biochemistry, vol. 102, 1980, pp. 255-270. [cited by applicant]
Brouwers et al., “Genetic Variability in Progranulin Contributes to Risk for Clinically Diagnosed Alzheimer Disease”, Neurology, vol. 71, 2008, pp. 656-664. [cited by applicant]
Carecchio et al., “Cerebrospinal Fluid Biomarkers in Progranulin Mutations Carriers”, Journal of Alzheimer's Disease, vol. 27, 2011, pp. 781-790. [cited by applicant]
Carrasquillo et al., “Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human Plasma”, The American Journal of Human Genetics, vol. 87, Dec. 10, 2010, pp. 890-897. [cited by applicant]
Chen et al., “Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway”, The Journal of Neuroscience, vol. 25, No. 26, Jun. 29, 2005, pp. 6156-6166. [cited by applicant]
Clackson et al., “Making Antibody Fragments Using Phage Display Libraries”, Nature, vol. 352, Aug. 15, 1991, pp. 624-628. [cited by applicant]
Cruts et al., “Loss of Progranulin Function in Frontotemporal Lobar Degeneration”, Trends Genetics, vol. 24, No. 4, 2008, pp. 186-194. [cited by applicant]
Degorce et al., “HTRF: A Technology Tailored for Drug Discovery—A Review of Theoretical Aspects and Recent Applications”, Current Chemical Genomics, vol. 3, 2009, pp. 22-32. [cited by applicant]
Egashira et al., “The Growth Factor Progranulin Attenuates Neuronal Injury Induced by Cerebral Ischemia-Reperfusion Through the Suppression of Neutrophil Recruitment”, Journal of Neuroinflammation, vol. 10, No. 105, 201… [cited by applicant]
Fellouse et al., “Synthetic Antibodies from a Four-Amino-Acid Code: A Dominant Role for Tyrosine in Antigen Recognition”, PNAS, vol. 101, No. 34, Aug. 24, 2004, pp. 12467-12472. [cited by applicant]
Fishwild et al., “High-Avidity Human lgGK Monoclonal Antibodies from a Novel Strain of Minilocus Transgenic Mice”, Nature Biotechnology, vol. 14, Jul. 1996, pp. 845-851. [cited by applicant]
Galimberti et al., “GRN Variability Contributes to Sporadic Frontotemporal Lobar Degeneration”, Journal of Alzheimer's Disease, vol. 19, 2010, pp. 171-177. [cited by applicant]
Gerngross, Tillman U., “Advances in the Production of Human Therapeutic Proteins in Yeasts and Filamentous Fungi”, Nature Biotechnology, vol. 22, No. 11, Nov. 2004, pp. 1409-1414. [cited by applicant]
Graham et al., “Characteristics of a Human Cell Line Transformed by DNA from Human Adenovirus Type 5”, Journal of General Virology, vol. 36, 1977, pp. 59-72. [cited by applicant]
Ham et al., “Media and Growth Requirements”, Methods in Enzymology, vol. LVIII, 1979, pp. 44-93. [cited by applicant]
Hongo et al., “Development and Characterization of Murine Monoclonal Antibodies to the Latency-Associated Peptide of Transforming Growth Factor β1”, Hybridoma, vol. 14, No. 3, 1995, pp. 253-260. [cited by applicant]
Hu et al., “Sortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin”, Neuron, vol. 68, Nov. 18, 2010, pp. 654-667. [cited by applicant]
Jakobovits et al., “Analysis of Homozygous Mutant Chimeric Mice: Deletion of The Immunoglobulin Heavy-chain Joining Region Blocks B-Cell Development and Antibody Production”, Proceedings of the National Academy of Scien… [cited by applicant]
Jakobovits et al., “Germ-line Transmission and Expression of a Human-derived Yeast Artificial Chromosome”, Nature, vol. 362, Mar. 18, 1993, pp. 255-258. [cited by applicant]
Kohler et al., “Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity”, Nature, vol. 256, Aug. 7, 1975, pp. 495-497. [cited by applicant]
Laird et al., “Progranulin is Neurotrophic in Vivo and Protects against a Mutant TDP-43 Induced Axonopathy”, PLoS ONE, vol. 5, No. 10, Oct. 2010, pp. 1-7. [cited by applicant]
Lee et al., “Bivalent Antibody Phage Display Mimics Natural Immunoglobulin”, Journal of Immunological Methods, vol. 284, 2004, pp. 119-132. [cited by applicant]
Lee et al., “High-affinity Human Antibodies from Phage-displayed Synthetic Fab Libraries with a Single Framework Scaffold”, Journal of Molecular Biology, vol. 340, 2004, pp. 1073-1093. [cited by applicant]
Lee et al., “Targeted Manipulation of the Sortilin-Progranulin Axis Rescues Progranulin Haploinsufficiency”, Human Molecular Genetics, vol. 23, No. 6, 2014, pp. 1467-1478. [cited by applicant]
Li et al., “Optimization of Humanized IgGs in Glycoengineered Pichia Pastoris”, Nature Biotechnology, vol. 24, No. 2, Feb. 2006, pp. 210-215. [cited by applicant]
Lonberg et al., “Antigen-Specific Human Antibodies from Mice Comprising Four Distinct Genetic Modifications”, Nature, vol. 368, Apr. 28, 1994, pp. 856-859. [cited by applicant]
Lonberg et al., “Human Antibodies from Transgenic Mice”, International Reviews of Immunology. vol. 13, 1995, pp. 65-93. [cited by applicant]
Marchetti et al., “Ligand-Induced Dynamics of Neurotrophin Receptors Investigated by Single-Molecule Imaging Approaches”, International Journal of Molecular Sciences, vol. 16, 2015, pp. 1949-1979. [cited by applicant]
Marks et al., “By-Passing Immunization: Building High Affinity Human Antibodies By Chain Shuffling”, Biotechnology, vol. 10, Jul. 1992, pp. 779-783. [cited by applicant]
Marks et al., “By-passing Immunization: Human Antibodies from V-gene Libraries Displayed on Phage”, Journal of Molecular Biology, vol. 222, 1991, pp. 581-597. [cited by applicant]
Martens et al., “Progranulin Deficiency Promotes Neuroinflammation and Neuron Loss Following Toxin-Induced Injury”, The Journal of Clinical Investigation, vol. 122, No. 11, Nov. 2012, pp. 3955-3959. [cited by applicant]
Mather et al., “Culture of Testicular Cells in Hormone-Supplemented Serum-Free Medium”, Annals of the New York Academy of Sciences, Testicular Cell Culture, 1982, pp. 44-68. [cited by applicant]
Mather, Jennie P., “Establishment and Characterization of Two Distinct Mouse Testicular Epithelial Cell Lines”, Biology of Reproduction, vol. 23, 1980, pp. 243-252. [cited by applicant]
Mazella et al., “Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design”, PLoS Biology, vol. 8, No. 4, Apr. 2010, pp. 1-17. [cited by applicant]
Mazella, et al., “The 100-kDa Neurotensin Receptor Is gp95/Sortilin, A Non-G-Protein-coupled Receptor”, The Journal of Biological Chemistry, vol. 273, No. 41, Oct. 9, 1998., pp. 26273-26276. [cited by applicant]
Morrison, Sherie L., “Success in specification”, Nature, vol. 368, Apr. 28, 1994, pp. 812-813. [cited by applicant]
Neuberger, Michael, “Generating high-avidity human Mabs in mice”, Nature Biotechnology, vol. 14, Jul. 1996, pp. 826. [cited by applicant]
Nykjaer et al., “Sortilin is Essential for proNGF Induced Neuronal Cell Death”, Nature, vol. 427, Feb. 26, 2004, pp. 843-848. [cited by applicant]
Nykjaer et al., “Sortilin: A Receptor to Regulate Neuronal Viability and Function”, Trends in Neurosciences, vol. 35, No. 4, Apr. 2012, pp. 261-270. [cited by applicant]
Petersen et al., “Propeptide Cleavage Conditions Sortilin/Neurotensin Receptor-3 for Ligand Binding”, The EMBO Journal, vol. 18, No. 3, 1999, pp. 595-604. [cited by applicant]
Pickford et al., “Progranulin Is a Chemoattractant for Microglia and Stimulates Their Endocytic Activity”, The American Journal of Pathology, vol. 178, No. 1, Jan. 2011, pp. 284-295. [cited by applicant]
Quistgaard et al., “Ligands Bind to Sortilin in the Tunnel of a Ten-Bladed β-Propeller Domain”, Nature Structural & Molecular Biology, vol. 16, No. 1, Jan. 2009, pp. 96-98. [cited by applicant]
Schrøder et al., “The Identification of AF38469: An Orally Bioavailable Inhibitor of the VPS10P Family Sorting Receptor Sortilin”, Bioorganic & Medicinal Chemistry Letters, vol. 24, 2014, pp. 177-180. [cited by applicant]
Sheng et al., “Progranulin Polymorphism rs5848 is Associated with Increased Risk of Alzheimer's Disease”, Gene, vol. 542, 2014, pp. 141-145. [cited by applicant]
Sidhu et al., “Phage-displayed Antibody Libraries of Synthetic Heavy Chain Complementarity Determining Regions”, Journal of Molecular Biology, vol. 338, Issue 2, Apr. 2004, pp. 299-310. [cited by applicant]
Sun et al., “FRET Microscopy in 2010: The legacy of Theodor Förster on the 100th Anniversary of his Birth”, Chemphyschem, vol. 12 No. 3, Feb. 25, 2011, pp. 462-474. [cited by applicant]
Tang et al., “The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic against Inflammatory Arthritis in Mice”, Science, vol. 332, Apr. 22, 2011, pp. 478-484. [cited by applicant]
Tao et al., “Neuroprotective Effects of Progranulin in Ischemic Mice”, Brain Research, vol. 1436, 2012, pp. 130-136. [cited by applicant]
Ullman et al., “Luminescent Oxygen Channeling Immunoassay: Measurement of Particle Binding Kinetics By Chemiluminescence”, Proceedings of the National Academy of Sciences, vol. 91, Jun. 1994, pp. 5426-5430. [cited by applicant]
Urlaub et al., “Isolation of Chinese Hamster Cell Mutants Deficient in Dihydrofolate Reductase Activity”, Proceedings of the National Academy of Sciences, vol. 77, No. 7, Jul. 1980, pp. 4216-4220. [cited by applicant]
Van Kampen et al., “Progranulin Gene Delivery Protects Dopaminergic Neurons in a Mouse Model of Parkinson's Disease”, PloS One, vol. 9, No. 5, 2014, pp. 1-10. [cited by applicant]
Yano et al., “Proneurotrophin-3 Is a Neuronal Apoptotic Ligand: Evidence for Retrograde-Directed Cell Killing”, The Journal of Neuroscience, vol. 29, No. 47, Nov. 25, 2009, pp. 14790-14802. [cited by applicant]
Yin et al., “Exaggerated Inflammation, Impaired Host Defense, and Neuropathology in Progranulin-Deficient Mice”, The Journal of Experimental Medicine, vol. 207, No. 1, Jan. 2010, pp. 117-128. [cited by applicant]
Zheng et al., “C-Terminus of Progranulin Interacts with the Beta-Propeller Region of Sortilin to Regulate Progranulin Trafficking”, PLoS One , vol. 6 , Issue 6 , Jun. 2011, 7 pages. [cited by applicant]
International Preliminary Report on Patentability received for PCT Patent Application No. PCT/US2016/026485, mailed on Oct. 19, 2017, 10 pages. [cited by applicant]
International Search Report and Written received for PCT Patent Application No. PCT/US2016/026485, mailed on Jul. 26, 2016, 13 pages. [cited by applicant]