Using Bugs as Drugs for MEPAN Syndrome

In November 2024 I came across a paper from the Tsvetkov Lab that discussed using bacteria to restore cellular protein lipoylation, which is a mitochondrial process required for enzymes in the TCA cycle and is impaired in people with MEPAN Syndrome.

Dr. Peter Tsvetkov is a cancer researcher at Harvard that studies lipoylation and cuproptosis, a form of cell death caused by an accumulation of copper in mitochondria. The concept of using “bugs as drugs” is an old concept from cancer research that is attracting new interest thanks to new molecular technologies like CRISPR-Cas9.

The mitochondrial fatty acid synthesis (mtFAS) pathway that is affected in MEPAN helps synthesize lipoic acid, which is an important cofactor for several mitochondrial enzyme complexes involving protein lipoylation and iron-sulfur cluster (Fe-S) synthesis.

Using cellular models in a lab, Tsvetkov’s work explored using an engineered bacterial enzyme as a potential treatment strategy for MEPAN Syndrome and similar disorders. The engineered enzyme - lipoate protein ligase A (lplA) - was shown to bypass the need for the complex de novo lipoylation pathway by scavenging free lipoic acid and attaching it directly to target proteins like MECR.

Because MEPAN Syndrome shares common mitochondrial defects with other lipoylation disorders (such as defects in Fe-S cluster biosynthesis or direct lipoylation pathways), this engineered bacterial enzyme could offer a generalized therapeutic solution for people with mutations in the genes associated with these disorders.

What was fascinating to me was that the paper described a patient with a mutation in the LIPT gene also had sideroblastic anemia - rare type of anemia characterized by an accumulation of iron in the mitochondria of immature red blood cells. I have long felt that other people with MEPAN may have abnormal blood cell levels or features of anemia like my sons, and for me, Tsvetkov’s work seems to help confirm that.

I contacted Dr. Tsvetkov and connected him with other MEPAN researchers to discuss his research and see if we could help advance it in some way. He is eager to test whether his engineered lplA enzyme will also work in a mammalian model, and both Children’s Hospital of Philadelphia and the University of Oulu have mouse models of MEPAN that mirror patient mutations in the MECR gene.

It was a rich discussion with some of the leading experts who study mtFAS – Drs. Alex Kastaniotis from the University of Oulu, Deborah Murdock from Children’s Hospital Philadelphia, and Sara Nowinski from the Van Andel Institute.

They touched on aspects of MEPAN and related disorders and the ways that the disease pathologies may intersect. Iron dysregulation was discussed as well, and it was pointed out from recent research that iron levels in MEPAN patient mitochondria might be abnormally elevated, but the iron levels in the cells themselves might lower. be low. There was also speculation about the optimal way to deliver the enzyme, possibly an AAV mediated delivery or a small molecule approach.

Hopefully the group will stay connected with Dr. Tsvetkov, and this method may someday help people with MEPAN and similar conditions. You can read more and access the paper here.