iPS in PD: How much and how soon?

iPS cell technologies hold the promise to change the way we look at regenerative medicine (cell replacement therapy) and drug development (disease modeling) in Parkinson’s disease. iPS cells have certainly  revitalized the dream of better drug development, disease modeling and regeneration by stem cells. Clearly, iPS cells are bringing an extremely fascinating biology to the stem cell field and, together with that, lots of excitement and very interesting biological questions that promise to lead to many new discoveries. Indeed, iPS cells offer important advantages and possibilities compared to embryonic stem (ES) cells, such as improving modeling of human disease in vitro, and avoiding ethical problems associated to the use of embryonic material or immunological issues associated to cell replacement therapy.  However, several challenges still lie ahead of us and several questions need to be addressed in order to develop new therapies for Parkinson’s disease, based on iPS technology.  These include:

1) How much do iPS cells differ amongst themselves and how much do they differ from ES cells at genetic and epigenetic levels? How important are these differences with regard to dopaminergic (DA) differentiation?

2) How relevant are the differences between human iPS cells and human ES cells for their functionality? In particular, as in vivo functionality is the ultimate test,  what is the functionality of human iPS cells in animal models of PD?

3) Does the re-expression of pluripotency genes have deleterious effects on the cell? It is for instance unknown whether expression or reactivation of transgenes or the re-expression of endogenous pluripotency genes may have an impact on the progeny of iPS cells. This may have consequences on the stability of both the dopaminergic phenotype and the disease model, and may increase the risk of tumor formation in cell replacement therapies.

4) How much of endogenous midbrain DA neuron development needs to be recapitulated in iPS/ES cell differentiation protocols in order to obtain appropriate models for drug development, cell replacement or disease models? Current protocols for DA differentiation of ES/iPS cells are good, but they could be much better if we improve our understanding of DA neuron development and we implement all that knowledge in iPS cultures. In fact, we do not know how many of the pathways activated during development may be relevant to disease mechanisms and whether they are required for disease modeling or for the in vivo maintenance of DA neurons after transplantation.

5) How good iPS cells will be as disease models? iPS technologies clearly offer advantages compared to ES cells in that by starting directly from patient material, endogenous pathological genetic alterations are captured by the cells. However, it remains unclear whether epigenetic alterations will be maintained or whether they can be reproduced after reprogramming of somatic cells. It is also unclear whether the mechanism of disease solely involves cell autonomous mechanisms, in which case, non-cell autonomous mechanisms will also need to be modeled. For instance, non-dopaminergic cells in the midbrain, the immune system, and environmental factors may contribute to PD. These factors may thus be required for modeling PD or for making reliable and clinically relevant in vitro models of disease.

In sum, it is at the moment impossible to determine how soon and how much of the expectation and the promise of iPS cells will materialize in PD models, drugs and therapies.  In fact, if we look at the recent history of stem cells, and in particular to their application to cell replacement in PD, it is probably fair to say that such developments will most likely take longer time than anticipated and desired. We thus have the dual responsibility of exercising caution, when communicating our excitement to the public, and putting our effort and resources to test, develop and apply this fascinating technology to drug development and cell replacement therapies for PD.