Mentor Areas
- Liver Cell/Gene therapy for the purpose of curing monogenetic disorders and also as a 'bridge to transplant'.
- Lentiviral transduction and/or gene targeting and/or drug mediated proliferation/differentiation of various types of stem cells, including mouse and human adult liver derived stem cells for the purpose of studying liver disease and for personalized drug screening.
Description:
Project 1: Liver Cell/Gene Therapy Using Drug Inducible Liver Derived Bipotent Ductal Stem Cells
While AAV (adeno associated virus) mediated liver gene therapy may be promising for some patients that were born with mendelian disorders resulting in loss of blood clotting factors XIII or IX, or factors involved in lipid metabolism (LDLR, LCAT), liver/lung homeostasis (A1AT), or the urea cycle (OTC), many patients with these disorders are not eligible for virus mediated gene therapy due to preexisting anti-AAV antibodies. In addition AAV is episomal and is diluted out in the growing liver of children, and to a lesser degree even during normal liver homeostasis, thus leading eventually to sub therapeutic transgene levels.
To address these serious problems we propose to completely replace AAV with patient liver-derived ductal stem cells as the vehicle for the therapeutic transgene. After introducing the transgene as well as our novel mammalian-derived genetic regulatory circuit into liver derived stem cells, they will be transplanted back into the liver, using the mouse as an initial model system. After engraftment, the regulatory circuit will allow their tight Tamoxifen- and Mifepristone-mediated expansion and differentiation, as needed for optimal and live long therapeutic transgene expression. Importantly, Tamoxifen and Mifepristone will be used at a ~20-50 fold lower concentration compared to their FDA approved indication, thus assuring minimal side effects which in turn should allow long term administration if necessary.
Project 2: Patient Liver Derived Bipotent Ductal Organoids for Liver Disease Modeling and Drug Screening
In collaboration with the Penn Transplant Center we have derived human bipotent ductal organoids directly from normal donor and patient liver and have been thoroughly characterizing them over the past year. We have shown for the first time that patient liver derived organoids can functionally model important disease characteristics of the patient liver from which they were isolated, such as lipid accumulation and inflammation - features of non-alcoholic hepatosteatitis and alcoholic liver disease which are highly prevalent world wide and can require liver transplantation if unchecked. We are actively pursuing ways to use these proliferating organoids for personalized drug screening that could be implemented in the clinic.
The student would aid in culturing/passaging/transducing patient derived organoids and subject them to drug screening for drugs that could alleviate liver disease symptoms and would also be involved in other important tests required for functional characterization, such as capacity to regenerate, lipid accumulation and inflammation.
Preferred Qualifications
- A strong interest organoid biology, gene/cell therapy and/or liver disease/metabolism
- Good chemistry skills
- Good mathematical skills
- In general, good 'hands on' skills in a lab setting
- Ability to productively interact with other lab members
Details:
Preferred Student Year
Second-Year, Junior, Senior
Academic Term
Fall, Spring, Summer
I prefer to have students start during the above term(s).Volunteer
No
Yes indicates that faculty are open to volunteers.Paid
No
Yes indicates that faculty are open to paying students they engage in their research, regardless of their work-study eligibility.Work Study
Yes
Yes indicates that faculty are open to hiring work-study-eligible students.