IP Library › Granted Patent US 12,290,500
Granted Patent B2
US 12,290,500 · App. 17/369,268 · Granted May 6, 2025

Anaplerotic agents for treatment of disorders of propionate and long chain fat metabolism

Inventors: Gerard Vockley (Pittsburgh, PA); Al-Walid A. Mohsen (Pittsburgh, PA)
Assignee: University of Pittsburgh—Of the Commonwealth System of Higher Education
A61K31/225A61P3/00C07C69/66
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 12,290,500
App. No.
17/369,268
Granted
May 6, 2025
Kind
B2
Abstract

Methods of treating propionic acidemia (PA), methylmalonic acidemia (MMA) and fatty acid oxidation disorders are described. The methods include administering an anaplerotic agent that can directly enter the tricarboxylic acid cycle, such as a succinate derivative or pro-drug, for example trisuccinylglycerol (TSG). Methods of restoring tricarboxylic acid (TCA) cycle function in a cell deficient for propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT) by contacting the cell with a succinate derivative or pro-drug, such as TSG, are also described.

Claims (12)

1. A method of restoring tricarboxylic acid (TCA) cycle function in a cell deficient for propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT), comprising contacting the cell with a compound of formula II

or a pharmaceutically acceptable salt or hydrate thereof, wherein each R 1 independently is H or a C 1-6 alkyl; each R 3 independently is a C 1-6 alkyl; and n is 1;

wherein the compound of formula II is the only therapeutic agent used in the method.

2. The method of claim 1 , wherein the method is an in vitro method.

3. The method of claim 1 , wherein the method is an in vivo method comprising administering the compound to a subject with a PCC or MUT deficiency.

4. The method of claim 3 , wherein the compound is administered to the subject once per day.

5. The method of claim 3 , wherein the compound is administered in multiple divided doses.

6. The method of claim 3 , wherein the compound is administered orally or intravenously.

7. The method of claim 3 , wherein each R 1 independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl or neopentyl.

8. The method of claim 3 , wherein each R 3 independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl or neopentyl.

9. The method of claim 1 , wherein each R 1 independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl or neopentyl.

10. The method of claim 1 , wherein each R 3 independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl or neopentyl.

Assignments (2)
CONFIRMATORY LICENSE Recorded Dec 6, 2023
From: UNIVERSITY OF PITTSBURGH
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065789/0117 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 7, 2021
From: VOCKLEY, GERARD; MOHSEN, AL-WALID A.
To: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
Reel/Frame 056777/0158 →
Continuity (3)
Division 16094828
Provisional Application 62324537 · Apr 19, 2016
Related Publication 20210338624A1 · Nov 4, 2021
References Cited (29)
US 9416364B2 · Gonzalez et al. · 2016 [cited by applicant]
US 10035819B2 · Evans et al. · 2018 [cited by applicant]
US 10253296B2 · Kahvejian et al. · 2019 [cited by applicant]
US 10301594B1 · Kahvejian et al. · 2019 [cited by applicant]
US 10344263B2 · Kahvejian et al. · 2019 [cited by applicant]
US 10442834B2 · Sajiki et al. · 2019 [cited by applicant]
US 10525029B2 · Jalan et al. · 2020 [cited by applicant]
US 20060241071A1 · Grinstaff et al. · 2006 [cited by applicant]
US 20120094293A1 · Spiegelman et al. · 2012 [cited by applicant]
US 20140343009A1 · Barth · 2014 [cited by applicant]
US 20150057363A1 · Miller et al. · 2015 [cited by applicant]
US 20150216824A1 · Mohamed et al. · 2015 [cited by applicant]
US 20200352894A1 · Levin · 2020 [cited by examiner]
WO WO2014053857A1 · 2014 [cited by examiner]
Ehinger et al. Nature communications 2016, 7, 12317, pp. 1-8. [cited by examiner]
“Anaplerotic Therapy in Propionic Acidemia,” NCT00645879, ClinicalTrials.gov, posted Mar. 28, 2008. [cited by applicant]
Baumgartner et al., “Proposed Guidelines for the Diagnosis and Management of Methylmalonic and Propionic Acidemia,” [cited by applicant]
Carrillo-Carrasco and Venditti, “Propionic Acidemia”, GeneReviews®—NCBI Bookshelf, posted May 17, 2012. [cited by applicant]
Celato et al., “A new case of malonic aciduria with a presymptomatic diagnosis and an early treatment Succinic acid,” [cited by applicant]
Goetzman et al., “Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction,” [cited by applicant]
International Search Report and Written Opinion mailed on Jun. 28, 2017 for International Application No. PCT/US2017/028100 (12 pages). [cited by applicant]
Park et al., “Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice,” [cited by applicant]
Price, Leisa Bitner, “Anaplerotic Therapy in Propionic Acidemia,” Thesis, College of Health, The University of Utah, May 2013. [cited by applicant]
† Roe & Brunengraber, “Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15 years Experience,” [cited by applicant]
Shchelochkov et al. (NIH, US Library of Medicine, National Center of Biotechnology Information, Propionic Acidemia Gene u Reviews, Initial Posting: May 17, 2012; Last Update: Oct. 6, 2016). [cited by applicant]
Teja et al. (Accession No. 2017:1316180, Hcaplus, Document No. 167:273685, Fluvestrant formulations, Abstract of Patent No. IN2012CH01418). [cited by applicant]
Vockley et al., “Long-term Major Clinical Outcomes in Patients with Long Chain Fatty Acid Oxidation Disorders Before and After Transition to Triheptanoin Treatment—A Retrospective Chart Review,” [cited by applicant]
Vockley, “Novel Therapies for Organic Acidemias”, 2016 FOD/OAA International Metabolic Family Conference, Westminister, Colorado, Jul. 8-9, 2016, downloaded from http://www.oaanews.org/uploads/8/7/3/7/87373510/oafmilypr… [cited by applicant]
Waisbren et al., “Neuropsychological Outcomes in Fatty Acid Oxidation Disorders: 85 Cases Detected by Newborn Screening,” [cited by applicant]