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Treating hyperammonemia with orally administered polymersomes

Applicant Leroux Jean-Christophe
Number 166697
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Pharmacology, Pharmacy
Start/End 01.11.2016 - 31.10.2019
Approved amount 443'674.00
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Keywords (4)

pharmaceutics; oral delivery; polymersomes; hyperammonemia

Lay Summary (German)

Lead
Die hepatische Enzephalopathie ist eine schwere Komplikation in Patienten mit eingeschränkter Leberfunktion. In diesem Projekt wird eine perorale Formulierung zur Behandlung dieser Krankheit entwickelt.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Die hepatische Enzephalopathie, eine weit verbreitete Komplikation in Patienten mit akutem Leberversagen und Zirrhose, ist eng verbunden mit einer eingeschränkten Fähigkeit der Leber, den neurotoxischen Metaboliten Ammoniak zu entgiften und erhöhte Blutammoniakspiegel (Hyperammonämie) zu vermeiden. Die Erkrankung präsentiert sich mit neuropsychiatrischen Symptomen und kann letal verlaufen. Zurzeit gültige Behandlungsleitlinien empfehlen prioritär Medikamente, welche die Ammoniakproduktion im Colon, der Hauptquelle systemischen Ammoniaks, vermindern, jedoch bei vielen Patienten nur beschränkt wirksam und verträglich sind. Dieses Projekt zielt darauf ab, eine perorale Formulierung zu finden, die Ammoniak im Dickdarm gezielt sequestriert und den Blutammoniakspiegel senkt. Verschiedene Formulierungen werden in magendarmtraktsimulierenden Flüssigkeiten auf ihre Fähigkeit zur Ammoniakbindung getestet und anschliessend in vivo evaluiert. Am Ende des Projekts wird die Erkenntnis stehen, ob die beste Formulierung Potenzial für eine ausführlichere präklinische und klinische Untersuchung hat.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

In diesem angewandten Forschungsprojekt werden Erkenntnisse der Pathophysiologie der hepatischen Enzephalopathie genutzt, um gezielt ein möglichst effektives, sicheres und simples Therapeutikum zu entwickeln.

 

Direct link to Lay Summary Last update: 02.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Engineered Polymersomes for the Treatment of Fish Odor Syndrome: A First Randomized Double Blind Olfactory Study
Schmidt Aaron C., Hebels Erik R., Weitzel Charlotte, Kletzmayr Anna, Bao Yinyin, Steuer Christian, Leroux Jean‐Christophe (2020), Engineered Polymersomes for the Treatment of Fish Odor Syndrome: A First Randomized Double Blind Olfactory Study, in Advanced Science, 1903697-1903697.
Ammonia uptake by transmembrane pH gradient poly(isoprene)- block -poly(ethylene glycol) polymersomes
Schmidt Aaron C., Hebels Erik R., Weitzel Charlotte, Stoessel Barbara, Bao Yinyin, Altmann Karl-Heinz, Leroux Jean-Christophe (2020), Ammonia uptake by transmembrane pH gradient poly(isoprene)- block -poly(ethylene glycol) polymersomes, in Soft Matter, 1-11.
An Investigation of PS‐ b ‐PEO Polymersomes for the Oral Treatment and Diagnosis of Hyperammonemia
Matoori Simon, Bao Yinyin, Schmidt Aaron, Fischer Eric J., Ochoa‐Sanchez Rafael, Tremblay Mélanie, Oliveira Mariana M., Rose Christopher F., Leroux Jean‐Christophe (2019), An Investigation of PS‐ b ‐PEO Polymersomes for the Oral Treatment and Diagnosis of Hyperammonemia, in Small, 1902347-1902347.

Collaboration

Group / person Country
Types of collaboration
Prof. Christopher Rose, Faculty of Medicine, University of Montreal Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
International Symposium on Biomedical Materials for Drug/Gene Delivery Talk given at a conference Vesicles as sequestering agents in biodetoxification 07.02.2020 Salt Lake City, United States of America Leroux Jean-Christophe;
12th SSCI Symposium Poster Engineered polymersomes for the treatment of fish odor syndrome 16.01.2020 Zürich, Switzerland Schmidt Aaron; Leroux Jean-Christophe; Bao Yinyin;
ACS National Meeting & Expo Poster Polymersomes for biodetoxification applications 25.08.2019 San Diego, CA, United States of America Schmidt Aaron; Leroux Jean-Christophe;
SF Nano, 5th Annual Meeting Talk given at a conference Vesicles - From treating cancer to liver diseases. 03.12.2018 Montpellier, France Leroux Jean-Christophe;
16th INTERNATIONAL NANOMEDICINE & DRUG DELIVERY SYMPOSIUM Poster Development of a novel polymersome-based ammonia assay 21.09.2018 Portland, United States of America Bao Yinyin; Leroux Jean-Christophe;
Swiss Pharma Science Day Poster Development of an Oral Polymersome Formulation for Ammonia Detoxification 22.08.2018 Bern, Switzerland Schmidt Aaron; Bao Yinyin; Leroux Jean-Christophe;
Bordeaux polymer conference Poster Polymersomes for biodetoxification applications 28.05.2018 Bordeaux, France Schmidt Aaron; Leroux Jean-Christophe;


Awards

Title Year
Best poster award, Swiss Pharma Science Day 2018 2018

Associated projects

Number Title Start Funding scheme
147651 Focused Ultrasound-Mediated Delivery of Encapsulated MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma 01.03.2014 Sinergia

Abstract

While intoxication with exogenous substances can severely tamper with the homeostasis of the human body, the latter itself can also be an unexpected reservoir of “poisons”. Organ failure, as well as inborn or acquired metabolic diseases, can undermine the body’s natural eliminating mechanisms, resulting in the accumulation of potentially toxic endogenous metabolites associated with serious morbidities. The blood level of ammonia, an important player in protein metabolism, is tightly controlled by metabolic detoxification processes in the liver. In patients with impaired liver function (e.g., liver cirrhosis), blood ammonia levels can be greatly increased (hyperammonemia), leading to neurotoxicity concomitant with serious and in certain cases fatal neuropsychiatric complications known as hepatic encephalopathy. Currently, the recommended first- and second-line treatments for hepatic encephalopathy are the non-absorbable disaccharide lactulose and the antibiotic rifaximin, respectively. These therapies address the bacterial production and intestinal absorption of ammonia in the colon, the main site of ammonia generation. Unfortunately, both therapies fail to control the symptoms and progression of hepatic encephalopathy in a considerable fraction of patients. Recently, we established the proof-of-concept of ammonia capture via liposome-supported peritoneal dialysis in vivo, where we demonstrated the capacity of transmembrane pH-gradient liposomes to sequester high amounts of systemic ammonia in a relatively selective fashion following intraperitoneal administration. The mechanism of action of pH-gradient vesicles is based on the diffusion of ammonia across the hydrophobic membrane and its subsequent protonation in the acidic core, where the positively charged ammonium remains trapped. However, this peritoneal dialysis approach may only be applied in acute life-threatening cases of hepatic encephalopathy (e.g., acute liver failure).In order to develop a maintenance treatment for cirrhotic patients with chronically elevated blood ammonia levels, the established strategy of ammonia sequestration by pH-gradient vesicles needs to be transposed to the gastrointestinal tract. Therefore, the main objective of this grant application is to develop vesicles to be administered via the oral route in order to trap ammonia in the colon, thereby reducing its intestinal absorption and ultimately lowering its concentration in the blood. In view of the harsh conditions found in the gastrointestinal tract (low pH, digestive enzymes), non-biodegradable polymersomes will be used instead of liposomes.As laid out in this proposal, we will first synthesize polymers reported to form non-biodegradable polymersomes and subsequently generate vesicles of different sizes using various methods. After a thorough investigation of the morphological properties and stability of the polymersomes in simulated gastrointestinal fluids, their capacity to capture and retain ammonia will be determined in vitro. Finally, the therapeutic potential of the best polymersome formulations will be investigated in vivo in bile duct-ligated rats, an established animal model of hepatic encephalopathy. The goal of this research is to develop an oral vesicle formulation with the capacity to capture ammonia in the gastrointestinal tract. We believe that this approach has great potential to become a first-line treatment for chronic and episodic hyperammonemia, and promises to alleviate the disease burden in patients suffering from hepatic encephalopathy.
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