Stem cell therapy for the treatment of achalasia and gastroparesis

Gastroparesis and achalasia are debilitating gastrointestinal disorders caused by the selective loss of nitrergic neurons (which contain neuronal nitric oxide synthase, nNOS) from the enteric nervous system in the stomach and oesophagus, respectively.

Patients suffer from severe abdominal pain, nausea, and have chronic long-term problems, including an increased risk of oesophageal cancer.

These are also some of the most challenging clinical conditions to manage, as there are currently no effective pharmacological treatments. Therefore, there is a lot of interest in the potential of stem cell therapy to replace missing enteric neurons, restore ENS circuitry and normal gut motility.

In this research project, we will apply the knowledge and techniques that we have developed to investigate the generation and transplantation of nNOS specific precursors for the treatment of achalasia and gastroparesis in an nNOS mouse model.

We hypothesise that transplanted nNOS precursors will integrate into the existing circuitry, communicate with muscle cells at the lower oesophageal sphincter (junction of oesophagus and stomach) and pylorus (junction of stomach and small intestinal) to restore normal motility.

Further, using knowledge gained from RNA sequence analysis of differentiation of nNOS neurons during embryonic development, we will program patient-derived induced pluripotent stem cells (iPSCs) into nNOS specific precursors for transplantation. This will be the first study to investigate stem cell therapy as a potential treatment for achalasia, and the first study to generate patient-derived nNOS precursors.

We will use the knowledge and techniques that we developed to investigate the transplantation of nNOS specific precursors for the treatment of a mouse model of gastroparesis and achalasia.

The project will be complemented by the project on Defects in long-distance neuronal wiring in the large intestine and in Hirschsprung’s Disease and the collaboration will ensure successful completion of the project.

Project goals

The key research questions in this project are:

• To investigate stem cell therapy as a potential treatment for achalasia, a condition where damaged nerves in the esophagus prevent it from allowing food to enter the stomach.
• To be the first study to generate patient-derived nitrergic neurons (which contain neuronal nitric oxide synthase, nNOS).
• To investigate integration of transplanted nNOS precursors with the recipient’s neuro-muscular network.
• To generate nNOS specific precursors from mice and patient-derived induced pluripotent stem cells (iPSCs).

Supervision team

The University of Melbourne: Dr Lincon Stamp, Dr Marlene Hao

KU Leuven: Professor Dr Pieter Vanden Berghe, Professor Dr Marc Miserez

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Who we are looking for

We are seeking a PhD candidate with the following skills:

• Demonstrated experience in the field of biomedical engineering/health sciences.
• Demonstrated ability to work independently and as part of a team.
• Demonstrated time and project management skills.
• Demonstrated ability to write research reports or other publications to a publishable standard (even if not published to date).
• Excellent written and oral communication skills.
• Demonstrated organisational skills, time management and ability to work to priorities.
• Demonstrated problem-solving abilities.