Recently, the US Food and Drug Administration (FDA) provided clearance to proceed with a Phase 2 clinical trial assessing HST5040 to treat children with propionic acidemia and methylmalonic acidemia, two rare inborn error of metabolism conditions that have limited treatment options. We talked with one of the principal investigators of the study, Marshall Summar, MD, Division Chief, Genetics and Metabolism and Director of the Rare Disease Institute at Children’s National Hospital.

Please describe propionic acidemia and methylmalonic acidemia.

Propionic acidemia and methylmalonic acidemia are two of the older inborn errors of metabolism, by that, I mean we’ve known about them for a pretty long time.  I think they were first described back in the 60s or 50s. So they’ve been with us a very long time.  They were also two of the triggers for expanded newborn screening, so being able to pick these patients up is one of the reasons people went to a broader platform tandem mass spectroscopy newborn screening back in the early 90s.

These are two diseases where biochemical intermediates, in other words somewhere about midway in a pathway you can’t get past a certain point and things build up,  and these organic acids have a high degree of toxicity. They shut down other metabolic pathways. They’ll interfere with the urea cycle function. They’ll interfere with bone marrow function. They will interfere with just basic energy metabolism.  So, they’re very tough diseases to treat and also very hard for these kids.

What are the current treatment options? 

The current state of the art treatment on these kids is trying to get things out of the diet that might feed these pathways—so reduction in protein and reduction in the branched chain amino acids, which are the primary feeders.

The problem with that is they still have to get those branched chains because they’re essential amino acids. The diet will help but it is really tough to do and also very prone to get out of balance.  So,  these are patients that we would call frequent flyers in the hospital—they’re in and out of the hospital a lot— we have some patients that will come in as much as once a month.

So, our treatment is first to try to remove the things that the kids can’t produce. We’ll try various cofactor supplements to see if we’ll gain some extra help there but that’s very plus minus on how much that helps. A lot of these kids end up going to liver transplant.  We sort of call that a poor man’s gene therapy.  We don’t have gene therapy that is in clinic right now for these kids, but maybe someday.

With liver transplant, we can certainly reduce the number of symptoms they have but we’ve traded one disease for another so that kind of gives you kind of a spectrum on how serious these things are for these kids, in and out of the hospital, with liver transplants about the best thing we have for the more serious ones.

What about HST5050 as a treatment option?

This has actually been kind of one of those fun and exciting science stories you get to do every so often in your career. We started working with the group in charlottesville at HemoShear, about four or five years ago.  The concept was is they had this beautiful cell model for working with liver cells to see how their biochemistry would work and they were working on drug metabolism.

We approached them with the idea that when we do liver transplant on our patients, we normally throw those livers away because you can’t transplant them into another patient. And so we teamed up with Dr Chapman, who worked on the science on this and I kind of worked more on the admin side,  and we took the livers from our patients with these organic acidemias, put them in their system  and used that to identify targets for therapy.  And we were actually quite successful with that.

So, there are two kinds of approaches going on in a lot of the biochemical disorders right now. One is nucleic acid therapies, and I think those are still a way off from really being a mainstream therapy for these patients,  although one can always hope. The other is  a small molecule approach, basically looking at pathway blockade, or inhibition, to try to remove toxic metabolites.  The nice thing about the way we worked this up is we were actually able to use cells from patients with the actual disease we’re going to be treating to see if it was effective in a human in vitro system before we started looking at patients. And  we’re able to find a compound that has already had a pretty good safety profile, so we were able to move that part forward pretty quickly.

A phase 2 clinical trial is currently being planned with that small molecule approach (HST5050). For more information, visit



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