Propionic Acidemia Clinical Trial
Official title:
Safety & Efficacy of Investigational Products: Ornithine Alpha-ketoglutarate, Glutamine, or Disodium Citrate on Hyperammonemia in Propionic Acidemia.
The objective of this project is to define whether nutritional supplements (ornithine alpha-ketoglutarate, glutamine, or citrate) capable of filling-up the citric acid cycle (anaplerotic therapy) can improve hyperammonemia, glutamine levels, and outcome in patients with propionic acidemia. Ornithine alpha-ketoglutarate, glutamine, and citrate are commonly used as nutritional supplements specially by athletes to increase muscle strength. They can be mixed with formula or other foods.
Propionic acidemia is caused by deficiency of propionyl CoA carboxylase that impairs the
supply of succinyl CoA to the citric acid (Krebs) cycle. The Krebs cycle is responsible for
obtaining energy from food in the form of ATP. ATP is essential for muscle contraction and
correct functioning of all organs including the hearth, the kidney, and the pancreas.
Patients with propionic acidemia develop hyperammonemia at birth that recurs during episodes
of metabolic decompensation. We found that plasma levels of the amino acids
glutamine/glutamate are reduced in patients with propionic acidemia and decrease, rather
than increase (like in urea cycle defects or other types of hyperammonemia) with
hyperammonemia. Since alpha-ketoglutarate is the main source of endogenous
glutamate/glutamine synthesis, our hypothesis is that chronic hyperammonemia and progressive
dysfunction of multiple organs in patients with propionic acidemia is due to a functional
insufficiency of the citric acid (Krebs) cycle with defective production of
alpha-ketoglutarate. The basic deficiency of intermediates of the Krebs cycle can decrease
production of ATP and explain the low muscle tone, progressive organ dysfunction, and poor
long-term outcome of patients with propionic acidemia.
To test this hypothesis, we will test whether dietary supplementation with alpha
ketoglutarate precursors (in the form of ornithine alpha ketoglutarate, glutamine or
citrate) can improve plasma ammonia and overall outcome in patients with propionic acidemia.
In this study, a limited number of patients (3) with propionic acidemia will be given the 3
different nutritional supplements and studied at regular intervals to see whether their
glutamine/glutamate levels improve and if they have fewer episodes of hyperammonemia or
acute decompensation. The supplement that produces the best increase in plasma glutamine
levels will be tested for an additional 30 weeks. Children's development and motor skills
will be tested before and after therapy to see if there is any improvement. The study will
be conducted on outpatients at the University of Utah Clinical Research Center. If the
initial trial is successful, we will try to launch a national trial involving multiple
centers in the US and abroad to involve the largest number of patients possible.
The current therapy of propionic acidemia is based on restriction of precursors of propionic
acid (methionine, valine, isoleucine, threonine, odd chain fatty acids, cholesterol) and
administration of carnitine to help remove toxic organic acids. This therapy is not
effective in preventing the long-term complications of the disease, even in children
identified at birth by newborn screening. This research will test a completely new way of
treating patients with severe and disabling metabolic disorders using replacement of
downstream products involved in the generation of energy (ATP). This approach, if effective,
could be extended to a number of other diseases, including other organic acidemias and
mitochondrial disorders.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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