IP Library › Granted Patent US 12,403,138
Granted Patent B2
US 12,403,138 · App. 17/778,369 · Granted Sep 2, 2025

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

Inventors: John M. Sedivy (Barrington, RI); Gerwald Jogl (Pawtucket, RI); Alexandra D'Ordine (Lakeville, MA)
Assignee: Brown University
A61K31/4741A61K31/145A61K31/166A61K31/167A61K31/17A61K31/198A61K31/366A61K31/381A61K31/4035A61K31/4192A61K31/423A61K31/445A61K31/505A61K31/53A61K31/635A61K31/64
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 12,403,138
App. No.
17/778,369
Granted
Sep 2, 2025
Kind
B2
Abstract

Disclosed is a method for preventing, delaying or reversing age-associated inflammation, by administering to a patient in need thereof a therapeutically effective amount of at least one LINE 1 (L-1) endonuclease inhibitor. The age-associated inflammation is associated with an upregulation of L1, an accumulation of cytoplasmic L1 cDNA, an activation of an IFN-I response, and/or a reinforcement of a SASP pro-inflammatory state. The L1 EN inhibitor is administered in an amount sufficient to prevent or reverse at least one of the upregulation L1, the accumulation of cytoplasmic L1 cDNA, the activation of the IFN-I response, and/or the SASP pro-inflammatory state.

Claims (9)

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 AD11 of the chemical structure shown below:

(AD11); and

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

2. The method of claim 1 , wherein the age-associated inflammation is associated with an upregulation of L1, an accumulation of cytoplasmic L1 cDNA, an activation of a type-I interferon (IFN-I) response, or a reinforcement of a Senescence-Associated Secretory Phenotype (SASP) pro-inflammatory state.

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

4. The method of claim 1 , wherein a decrease in one or more symptoms of the Alzheimer's disease is determined using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog).

5. The method of claim 1 , wherein a decrease in one or more symptoms of the Alzheimer's disease is determined using the Clinician's Interview-Based Impression of Change (CIBIC-plus).

6. The method of claim 1 , wherein a decrease in one or more symptoms of the Alzheimer's disease is determined using the Activities of Daily Living Scale (ADL).

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

Assignments (2)
LICENSE Recorded Nov 25, 2024
From: BROWN UNIVERSITY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 069439/0020 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2022
From: SEDIVY, JOHN M.; JOGL, GERWALD; D'ORDINE, ALEXANDRA
To: BROWN UNIVERSITY
Reel/Frame 061950/0270 →
Continuity (3)
Provisional Application 63077888 · Sep 14, 2020
Provisional Application 62939564 · Nov 22, 2019
Related Publication 20230139684A1 · May 4, 2023
References Cited (38)
US 5859037A · Whitcomb · 1999 [cited by examiner]
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 applicant]
WO WO2008046014A1 · 2008 [cited by examiner]
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. 93479-97-1. Retrieved from SciFinder (Feb. 13, 2024). pp. 1-2. (Year: 2024). [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, Nov. 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]
“CAS Registry No. 1197-18-8 (“Tranexamic Acid”)”, Retrieved from SciFinder Sep. 14, 2024, pp. 1-3. [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]
D'Ordine, et al., “Identification and Characterization of Small Molecule Inhibitors of the LINE-1 Retrotransposon Endonuclease”, bioRxiv preprint, Dec. 29, 2022, 16 pages. [cited by applicant]
Hiramoto, et al., “Tranexamic Acid Improves Memory and Learning Abilities in Aging Mice”, Journal of Experimental Pharmacology, vol. 12, 2020, pp. 653-663. [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]