Treatments of trimethylaminuria: where we are and where we might be heading.

Trimethylamine (TMA) is a volatile, foul-smelling, diet-derived amine, primarily generated in the colon and metabolized in the liver to its odorless N-oxide (TMAO). In primary trimethylaminuria (TMAU), an inherited deficiency in flavin-containing monooxygenase 3 leads to elevated systemic TMA levels. The excretion of elevated amounts of TMA in sweat, breath, urine and other bodily secretions gives individuals affected by TMAU a smell resembling that of rotten fish. Although the disorder might not seem an important health problem, its social and psychological burden can be devastating. To date, no treatment modifying the disorder exists and only a few pharmacological therapies provide modest and transient benefits. This review provides an overview of investigated TMAU treatments and outlines promising new research directions.

Engineered Polymersomes for the Treatment of Fish Odor Syndrome: A First Randomized Double Blind Olfactory Study.

Trimethylamine (TMA) is a metabolite overtly present in patients suffering from trimethylaminuria (TMAU), a rare genetic disorder characterized by a strong "fishy" body odor. To date, no approved pharmacological treatment to sequester excess TMA on the skin of patients exists. Here, transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes are investigated for the topical removal of TMA. PI-b-PEG amphiphiles of varying chain length are synthesized and evaluated for their ability to form vesicular structures in aqueous media. The optimization of the PI/PEG ratio of transmembrane pH gradient polymersomes allows for the rapid and efficient capture of TMA both in solution and after incorporation into a topical hydrogel matrix at the pH of the skin. A subsequent double blind olfactory study reveals a significant decrease in perceived odor intensity after application of the polymersome-based formulation on artificial skin substrates that has been incubated in TMA-containing medium. This simple and novel approach has the potential to ease the burden of people suffering from TMAU.

Ammonia uptake by transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) polymersomes.

Transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes were investigated for their potential use in the detoxification of ammonia, a metabolite that is excessively present in patients suffering from urea cycle disorders and advanced liver diseases, and which causes neurotoxic effects (e.g., hepatic encephalopathy). Polymers varying in PI and PEG block length were synthesized via nitroxide-mediated polymerization and screened for their ability to self-assemble into polymersomes in aqueous media. Ammonia sequestration by the polymersomes was investigated in vitro. While most vesicular systems were able to capture ammonia in simulated intestinal fluids, uptake was lost in partially dehydrated medium mimicking conditions in the colon. Polymeric crosslinking of residual olefinic bonds in the PI block increased polymersome stability, partially preserving the ammonia capture capacity in the simulated colon environment. These more stable vesicular systems hold promise for the chronic oral treatment of hyperammonemia.