IP Library › Granted Patent US 12,350,264
Granted Patent B2
US 12,350,264 · App. 18/537,765 · Granted Jul 8, 2025

Compositions and methods for treating, preventing or reversing age-associated inflammation and disorder

Inventors: John M. Sedivy (Barrington, RI); Gerwald Jogl (Pawtucket, RI); Alexandra D'Ordine (Lakeville, MA)
Assignee: Brown University
A61K31/4741A61K31/136A61K31/145A61K31/166A61K31/167A61K31/17A61K31/19A61K31/192A61K31/194A61K31/195A61K31/196A61K31/366A61K31/381A61K31/4015A61K31/4035A61K31/4192A61K31/423A61K31/433A61K31/437A61K31/445A61K31/4704A61K31/50A61K31/501A61K31/505A61K31/506A61K31/517A61K31/519A61K31/53A61K31/554A61P29/00
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 12,350,264
App. No.
18/537,765
Granted
Jul 8, 2025
Kind
B2
Abstract

Disclosed are methods for preventing, delaying or reversing age-associated inflammation, by administering to a patient in need thereof a therapeutically effective amount of at least one long interspersed nuclear element 1 (LINE-1, L1) endonuclease inhibitor (L1 EN inhibitor), either alone or in combination with at least one additional therapeutic agent. Effectiveness of the methods can be measured via biomarkers and/or by a decrease in symptoms compared to those symptoms before administration of the L1 EN inhibitor. Specific chemical structures of the L1 EN inhibitors are identified and shown herein.

Claims (6)

1. A method for treating an age-associated inflammation in a patient in need thereof, the method comprising administering a therapeutically effective amount of a long interspersed nuclear element-1 (L1) endonuclease (EN) inhibitor to the patient; wherein the L1 EN inhibitor is AD34 of the chemical structure shown below:

and

wherein the age-associated inflammation is in a patient having Alzheimer's disease.

2. The method of claim 1 , wherein the patient experiences a decrease in one or more symptoms of the Alzheimer's disease after the administration of the AD34 to the patient; and wherein the decrease in the one or more symptoms is evaluated according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5).

3. The method of claim 1 , wherein the patient experiences a decrease in one or more symptoms of the Alzheimer's disease after the administration of the AD34 to the patient; and wherein the decrease of one or more symptoms is determined using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Clinician's Interview-Based Impression of Change (CIBIC-plus), or the Activities of Daily Living Scale (ADL).

4. The method of claim 1 , further comprising an administering of at least one second therapeutic agent to the patient.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 29, 2023
From: SEDIVY, JOHN M.; JOGL, GERWALD; D'ORDINE, ALEXANDRA
To: BROWN UNIVERSITY
Reel/Frame 065977/0730 →
Continuity (5)
Continuation In Part 17778369
Provisional Application 63387188 · Dec 13, 2022
Provisional Application 63077888 · Sep 14, 2020
Provisional Application 62939564 · Nov 22, 2019
Related Publication 20240207249A1 · Jun 27, 2024
References Cited (38)
US 5859037A · Whitcomb · 1999 [cited by applicant]
US 9624235B2 · Gold et al. · 2017 [cited by applicant]
US 10100307B2 · Prochiantz et al. · 2018 [cited by applicant]
US 20070189967A1 · Siclovan et al. · 2007 [cited by applicant]
US 20100029654A1 · Pasinetti · 2010 [cited by examiner]
WO 2008046014A1 · 2008 [cited by applicant]
WO 2017004436A2 · 2017 [cited by applicant]
WO 2018136920A1 · 2018 [cited by applicant]
WO 2020154656A1 · 2020 [cited by applicant]
WO 2021102423A1 · 2021 [cited by applicant]
WO 2022197689A1 · 2022 [cited by applicant]
CAS Registry No. 1197-18-8 (“Tranexamic Acid”). Retrieved from SciFinder Sep. 14, 2024. pp. 1-3. (Year: 2024). [cited by examiner]
Hiramoto et al. “Tranexamic Acid Improves Memory and Learning Abilities in Aging Mice”. Journal of Experimental Pharmacology. 2020; 12:653-663. (Year: 2020). [cited by examiner]
“Discussion Paper on the Clinical Investigation of Medicines for the Treatment of Alzheimer's Disease and Other Dementias”, European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), Oct. 23, 2014… [cited by applicant]
“International Search Report and Written Opinion received for PCT Patent Application No. PCT/US2020/061842, mailed on Mar. 31, 2021”, 14 pages. [cited by applicant]
Allen , et al., “Dock 6: Impact of New Features and Current Docking Performance”, Journal of Computational Chemistry, vol. 36, 2015, pp. 1132-1156. [cited by applicant]
Banuelos-Sanchez , et al., “Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons”, Cell Chemical Biology, vol. 26, Issue 8, Aug. 15, 2019, 30 pages. [cited by applicant]
Dai , et al., “Effect of Reverse Transcriptase Inhibitors on LINE-1 and Ty1 Reverse Transcriptase Activities and on LINE-1 Retrotransposition”, BMC Biochemistry, vol. 12, No. 18, 2011, 11 pages. [cited by applicant]
De Cecco , et al., “Genomes of Replicatively Senescent Cells Undergo Global Epigenetic Changes Leading to Gene Silencing and Activation of Transposable Elements”, Aging Cell, vol. 12, 2013, pp. 247-256. [cited by applicant]
De Cecco , et al., “L1 Drives IFN in Senescent Cells and Promotes Age-Associated Inflammation”, Nature, vol. 566,, Feb. 2019, 33 pages. [cited by applicant]
De Cecco , et al., “Transposable Elements Become Active and Mobile in the Genomes of Aging Mammalian Somatic Tissues”, Aging, vol. 5, No. 12, Dec. 2013, pp. 867-883. [cited by applicant]
Deleidi , et al., “Immune Aging, Dysmetabolism, and Inflammation in Neurological Diseases”, Frontiers in Neuroscience, vol. 9, No. 172, Jun. 3, 2015, pp. 1-14. [cited by applicant]
Feng , et al., “Design and Activity of AP Endonuclease-1 Inhibitors”, Journal of Chemical Biology, vol. 8, 2015, pp. 79-93. [cited by applicant]
Feng , et al., “Human L1 Retrotransposon Encodes a Conserved Endonuclease Required for Retrotransposition”, Cell, vol. 87, Nov. 29, 1996, pp. 905-916. [cited by applicant]
Gold , et al., “Safety and Tolerability of Triumeq in Amyotrophic Lateral Sclerosis: The Lighthouse Trial”, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019, pp. 1-10. [cited by applicant]
Liu, et al., “Loss of Nuclear TDP-43 is Associated with Decondensation of LINE Retrotransposons”, Cell Reports 27, Apr. 30, 2019, 20 pages. [cited by applicant]
Lopez-Otin , et al., “The Hallmarks of Aging”, Cell, vol. 153, Jun. 6, 2013, pp. 1194-1217. [cited by applicant]
Ostertag , et al., “Biology of Mammalian L1 Retrotransposons”, Annual Review of Genetics, vol. 35, 2001, pp. 501-538. [cited by applicant]
Srinivasan , et al., “Identification and Characterization of Human Apurinic/Apyrimidinic Endonuclease-1 Inhibitors”, Biochemistry, vol. 51, No. 31, 2012, pp. 6246-6259. [cited by applicant]
Trott , et al., “AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading”, Journal of Computational Chemistry, vol. 31, No. 2, 2010, pp. 455-461. [cited by applicant]
Tyagi , et al., “Inhibition of Human Endogenous Retrovirus-K by Antiretroviral Drugs”, Retrovirology, vol. 14, No. 21, 2017, 13 pages. [cited by applicant]
Weichenrieder , et al., “Crystal Structure of the Targeting Endonuclease of the Human LINE-1 Retrotransposon”, Structure, vol. 12, No. 6, 2004, pp. 975-986. [cited by applicant]
Xie , et al., “Characterization of L1 Retrotransposition with High-Throughput Dual-Luciferase Assays”, Nucleic Acids Research, vol. 39, No. 3, e16, 2011, 11 pages. [cited by applicant]
Zhang , et al., “Enriching Screening Libraries with Bioactive Fragment Space”, Bioorganic & Medicinal Chemistry Letters, vol. 26, No. 15, 2016, 12 pages. [cited by applicant]
D'Ordine , et al., “Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease”, bioRxiv preprint doi: https://doi.org/10.1101/2022.12.29.522256, Dec. 29, 2022, 16 pages. [cited by applicant]
Miller , et al., “Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease”, Nucleic Acids Research, vol. 49, No. 19, Sep. 23, 2021, pp. 11350-11366. [cited by applicant]
“CAS Registry No. 93479-97-1”, Retrieved from SciFinder on Feb. 13, 2024, pp. 1-2. [cited by applicant]
“International Search Report and Written Opinion received for PCT Patent Application No. PCT/US2023/083704, mailed on May 10, 2024”, 12 pages. [cited by applicant]