Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
- Experimental Therapies
- Experimental Therapies
Long chain fatty acid oxidation disorder (LCFAOD) is a group of genetic metabolic disorders characterized by impaired fat metabolism and energy deficiency. There are different types of LCFAOD based on the defective enzymes that lead to the impairment of long chain fatty acid metabolism.1
There is currently no cure for any type of LCFAOD but there are some treatments available such as carnitine supplementation, ketone body replacement, and triheptanoin that can be used to manage the disease.
Read more about LCFAOD treatments.
There are also a number of experimental approaches in the pipeline that attempt to treat or manage LCFAODs. These experimental treatments cover three basic strategies. They are nutritionally bypassing the defective enzyme to provide energy, increasing the expression of a semi-active enzyme variant, and boosting enzymatic activity by modulating post-translational modifications.2
One way to bypass the defective enzyme in LCFAOD is to use triheptanoin as an energy source. Triheptanoin is a 7-carbon chain triglyceride, which once ingested is broken down into free heptanoate. Heptanoate can then be metabolized by short- and medium-chain fatty acid oxidation enzymes thereby bypassing the defective long chain fatty acid metabolism enzymes.3
Triheptanoin has already been approved by the US Food and Drug Administration (FDA) to treat children and adults with LCFAODs.4
A study will soon start enrolling up to 300 patients to assess the long-term safety (up to 10 years) as well as pregnancy, infant, and lactation outcomes of triheptanoin treatment. Researchers will assess the incidence of any serious or non-serious adverse events during pregnancy for patients with LCFAOD and in nursing mothers and their breast-milk-fed infants. It will also assess neonate and infant outcomes from pregnancy throughout the first year of life and any incidence of colon cancer or gastrointestinal cancer, dysplasia, and neoplasia.5
The study sponsored by Ultragenyx Pharmaceutical Inc. is expected to be completed in March 2031.5
Increased Enzyme Expression
Research has shown that bezafibrate, a lipid-regulating drug used to treat hyperlipidemia, could increase the expression of very-long-chain acyl-CoA dehydrogenase (VLCAD) mRNA and protein llevels in fibroblast cultures. Bezafibrate was, therefore, considered a potential new therapy for LCFAOD.6
The effect of bezafibrate on metabolism during exercise was then assessed in 22 adults with carnitine palmitoyltransferase II (CPTII) or VLCAD deficiency in a phase 2 clinical trial.7 However, the results showed that bezafibrate did not improve clinical symptoms of fatty acid oxidation.8
Modulation of Post-Translational Modifications
It is known that all enzymes involved in fatty acid oxidation undergo multiple post-translational modifications such as acetylation, succinylation, glutarylation, ubiquitylation, phosphorylation, nitrosylation, and methylation.2
For example, trifunctional protein (TFP), which is involved in the beta-oxidation of long chain fatty acids in the mitochondria was known to undergo 173 unique modifications post-translationally.2
VLCAD also undergoes post-translational modifications such as lysine acetylation and succinylation and cysteine nitrosylation that change its activity and determine its ability to bind to cardiolipin on the inner membrane of the mitochondria, thereby influencing its localization inside the mitochondria.9,10
The modulation of post-translational modification as a potential treatment option for LCFAODs is in its infancy but offers promise. A proof-of-principle study showed that treating fibroblast from patients with VLCAD deficiency with a compound that induces cysteine nitrosylation could increase enzymatic activity 7 to 10 fold.11
More research is needed to fully explore the potential of post-translational modification modulation in treating LCFAODs.
Gene therapy is another potential approach that could be used to treat certain types of LCFAOD. The approach is being explored for the treatment of VLCAD deficiency the most common form of LCFAOD in humans.12
The approach has already been tested in mouse models of LCFAODs. For example, a laboratory at UMASS Medical School is currently comparing two viral vectors, rAAV1 and rAAV9 to assess their effectiveness in molecularly and biochemically correcting VLCAD deficiency. The laboratory is developing toxicology studies of muscle delivery of rAAV9 or rAAV1-VLCAD in anticipation of Phase I clinical trials to test the gene therapy approach for the treatment of fatty acid oxidation disorders in humans.13
- Vockley J. Long-chain fatty acid oxidation disorders and current management strategies. Am J Manag Care. 2020;26(7 Suppl):S147-S154. doi:10.37765/ajmc.2020.88480
- Goetzman ES. Advances in the understanding and treatment of mitochondrial fatty acid oxidation disorders. Curr Genet Med Rep. 2017;5(3):132-142. doi:10.1007/s40142-017-0125-6
- Sun A, Merritt II JL. Orphan drugs in development for long-chain fatty acid oxidation disorders: challenges and progress. Orphan Drugs: Research and Reviews. 2015;5:33-41. doi:10.2147/ODRR.S63061
- Ultragenyx announces US FDA approval of dojolvi™ (UX007/triheptanoin), the first FDA-approved therapy for the treatment of long-chain fatty acid oxidation disorders. News Release. Ultragenyx Pharmaceutical. June 30, 2020.
- Long-chain fatty acid oxidation disorders in-clinic disease monitoring program. US National Library of Medicine. Last update posted: May 24, 2021. Accessed: July 16, 2021.
- Djouadi F, Aubey F, Schlemmer D, et al. Bezafibrate increases very-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders. Hum Mol Genet. 2005;15;14(18):2695-703. doi:10.1093/hmg/ddi303
- Effect of ezafibrate on muscle metabolism in patients with fatty acid oxidation defects (bezafibrate). US National Library of Medicine. Last update posted: May 30, 2012. Accessed: July 16, 2021.
- Ørngreen MC, Madsen KL, Preisler N, Andersen G, Vissing J, Laforêt P. Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial. Neurology. 2014;82(7):607-613. doi:10.1212/WNL.0000000000000118
- Zhang Y, Bharathi SS, Rardin MJ, et al. SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS One. 2015;10(3):e0122297. doi:10.1371/journal.pone.0122297
- Doulias PT, Tenopoulou M, Greene JL, Raju K, Ischiropoulos H. Nitric oxide regulates mitochondrial fatty acid metabolism through reversible protein S-nitrosylation. Sci Signal. 2013;1;6(256):rs1. doi:10.1126/scisignal.2003252
- Tenopoulou M, Chen J, Bastin J, Bennett MJ, Ischiropoulos H, Doulias PT. Strategies for correcting very long chain acyl-CoA dehydrogenase deficiency. J Biol Chem. 2015;17;290(16):10486-94. doi:10.1074/jbc.M114.635102
- Keeler AM, Flotte TR. Cell and gene therapy for genetic diseases: inherited disorders affecting the lung and those mimicking sudden infant death syndrome. Hum Gene Ther. 2012;23(6):548-556. doi:10.1089/hum.2012.087
- Flotte Lab. Horae Gene Therapy Center. UMASS Medical School. Accessed July 16, 2021.
Reviewed by Harshi Dhingra, MD, on 7/17/2021.