US 12,352,767 B2
Method of treating cognitive decline associated with neurological diseases based on a decrease in FLT4 expression or activity
Jonathan Kipnis, Charlottesville, VA (US); and Sandro Da Mesquita, Charlottesville, VA (US)
Assigned to University of Virginia Patent Foundation, Charlottesville, VA (US)
Appl. No. 17/260,023
Filed by University of Virginia Patent Foundation, Charlottesville, VA (US)
PCT Filed Jul. 15, 2019, PCT No. PCT/US2019/041882
§ 371(c)(1), (2) Date Jan. 13, 2021,
PCT Pub. No. WO2020/018461, PCT Pub. Date Jan. 23, 2020.
Claims priority of provisional application 62/865,035, filed on Jun. 21, 2019.
Claims priority of provisional application 62/778,801, filed on Dec. 12, 2018.
Claims priority of provisional application 62/698,859, filed on Jul. 16, 2018.
Prior Publication US 2021/0311076 A1, Oct. 7, 2021
Int. Cl. G01N 33/68 (2006.01)
CPC G01N 33/6896 (2013.01) [G01N 2500/10 (2013.01); G01N 2800/2821 (2013.01); G01N 2800/50 (2013.01); G01N 2800/52 (2013.01); G01N 2800/60 (2013.01)] 13 Claims
 
1. A method of treating a subject afflicted with cognitive decline wherein the cognitive decline is a neurological disease, the method comprising:
a) obtaining a biological sample from the subject, wherein the sample is from the meninges of the subject;
b) determining the copy number, level of expression, or level of activity of FLT4 in the subject sample;
c) comparing the copy number, level of expression, or level of activity of said FLT4 detected in steps b) to the copy number, level of expression, or level of activity of FLT4 in a control;
wherein a significant decrease in the copy number, level of expression, or level of activity of FLT4 in the subject sample relative to the control copy number, level of expression, or level of activity of FLT4 indicates that the subject is afflicted with or is at risk for developing cognitive decline resulted from or is characterized by an aberrant decrease in meningeal lymphatic drainage and/or accumulated amyloid beta plaques; and
d) administering to a meningeal space or the central nervous system of the subject in need an effective amount of an agent that increases the level of expression or level of activity of FLT4, wherein the agent comprises:
(i) a nucleic acid molecule comprising a nucleotide sequence encoding FLT4;
(ii) an expression vector comprising a nucleotide sequence encoding FLT4; or
(iii) VEGF-C or VEGF-C156S;
(iv) a nucleic acid molecule comprising a nucleotide sequence encoding VEGF-C or VEGF-C126S; or
(v) an expression vector comprising a nucleotide sequence encoding VEGF-C or VEGF-C126S.