Lorenz Studer Talks About the Rare Genetic Disorder Familial Dysautonomia

New Hot Paper Commentary, January 2011

Lorenz Studer

Article: Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs

Authors: Lee, G;Papapetrou, EP;Kim, H;Chambers, SM;Tomishima, MJ;Fasano, CA;Ganat, YM;Menon, J;Shimizu, F;Viale, A;Tabar, V;Sadelain, M;Studer, L
Journal: NATURE
Volume: 461, Issue: 7262, Page: 402-U100, Year: SEP 17 2009
* Sloan Kettering Inst, Dev Biol Program, 1275 York Ave, New York, NY 10065 USA.
* Sloan Kettering Inst, Ctr Cell Engn, New York, NY 10065 USA.
(Addresses have been truncated)

Lorenz Studer talks with ScienceWatch.com and answers a few questions about this month's New Hot Papers paper in the Multisciplinary field.

SW: Why do you think your paper is highly cited?

The isolation of iPS cells by Shinya Yamanaka has been one of the seminal discoveries in biology. A key application is the potential use of patient-specific iPS cells to model disease in a dish. Our study was among the first to realize this idea going from iPS cell generation, differentiation into disease relevant cells, and identification of multiple disease-related phenotypes all the way to testing candidate drugs that can rescue such disease phenotypes. Therefore our work is now often cited as a "classic" example of what iPS cell-based disease modeling can achieve today.

SW: Does it describe a new discovery, methodology, or synthesis of knowledge?

The work represents both "synthesis of knowledge" and "new discovery." The "synthesis of knowledge" refers to combining existing technologies such as iPS cell induction and directed differentiation in novel ways to establish the disease model of familial dysautonomia (FD). The "new discovery" part relates to uncovering novel aspects of how FD causes the specific disease symptoms.

SW: Would you summarize the significance of your paper in layman's terms?

FD is a rare genetic disorder that is characterized by multiple defects, particularly in the peripheral nervous system, derived from a developmental structure called neural crest. While the gene causing the disease has been identified for nearly 10 years, the mechanism by which the genetic defect causes the specific disease symptoms has remained mysterious.

Our study offered a novel way to study the disease and to actually "test-run" the disease in a Petri dish. Using FD-iPS cells we generated many different tissue cell types and tested them for aspects of the disease such as splicing (processing) of the FD gene product. When we looked more closely at neural crest cells derived from the FD-iPS cells we found two additional interesting disease phenotypes (defect in generating autonomic nerve cells and defect in the motility of FD-derived cells).

With now three robust phenotypes in our hands, we started testing candidate drugs to see whether any compound can reverse the disease phenotypes. As it turned out the plant hormone kinetin was indeed able to reverse multiple disease phenotypes in our iPS system.

"Our screening strategy involved testing most currently FDA-approved drugs."

In the context of FD our work offers novel insights into the mechanism of disease and in particular the generation of autonomic neurons that—based on our data—appears defective very early on. The study also provides the basis for many additional mechanistic studies as we can now produce unlimited numbers of patient specific cells, many of which—for obvious reasons—cannot be directly harvested from patients. The data on kinetin, the compound effective at reversing disease phenotypes, may have direct relevance for clinical trials using this compound. Finally we think that the system will be a powerful tool to discover new drugs that may be even more potent than kinetin.

In more general terms the study offers an important proof-of-concept showing that it is feasible to capture aspects of disease in a Petri dish using iPS cell technology and that such disease phenotypes can give interesting information about the therapeutic potential of candidate drugs. Such an early proof-of-concept is valuable to stimulate research in the scientific community with the goal of pursuing similar strategies for a broad range of other disorders.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

My lab has worked for many years on how to coax human embryonic stem cells into specific cell types. With the discovery of iPS cells it became clear to me immediately that we were in an excellent position to use our expertise towards establishing human iPS cell based disease models. The specific choice of FD was based on a combination of factors. There were some important factors such as feasibility (we knew how to make the relevant cell types), and likelihood of finding a disease phenotype (we expected to see tissue specific splicing phenotype).

However, a less obvious point was how I first learned about the disease. As it turned out, nearly 10 years ago, I was helping to review grants for the National Institutes of Health (NIH). One of grants I was assigned to dealt with FD and I got fascinated by the mechanistic questions raised for this disease. While I did not work on FD for the next seven years or so, I recalled the disorder when thinking about disease modeling using iPS cells.

During that time I had an extremely talented postdoc, Gabsang Lee, who just had figured out how to generate neural crest stem cells and other neural crest derivatives from human ES cells. We also started a very successful collaboration with the lab of Michel Sadelain at our institute. In particular, Eirini Papapetrou, an excellent postdoc in the Sadelain lab, was among the first to routinely generate human iPS cells. She had developed a set of very elegant lentiviral reprogramming vectors for use in our study.

The study went remarkably smooth from the time of conception all the way to publication. We clearly had a few setbacks on the road such as difficulties to rescue some of the phenotypes such as the generation of ASCL1/Mash1+ cells. This lasted until Gabsang figured out that continuous exposure of the cells to kinetin, throughout differentiation, is required to do the trick. However, compared to most any other study in the lab, there were remarkably few setbacks in this study, and we moved forward very rapidly and without any major "hiccups."

In contrast, some of the next steps that we are currently pursuing have been much more challenging. For example, we are working on gene targeting to correct the FD mutation and on performing high-throughput screens testing thousands of compounds, including a library of most FDA-approved drugs in patient-specific neural crest cells. While we are making very good progress in both projects, the speed of progress is definitely slower than for our initial study.

SW: Where do you see your research leading in the future?

"Our study was among the first to realize this idea going from iPS cell generation, differentiation into disease relevant cells, and identification of multiple disease-related phenotypes all the way to testing candidate drugs that can rescue such disease phenotypes..."

For FD patients, I hope we will continue to contribute to a better understanding of the disease and its various clinical manifestations. But most importantly, we hope to find novel drugs that will directly benefit the patients. FD is a disease for which currently no effective drugs are available.

Interestingly, the compound kinetin that was shown to be effective in our iPS cell model has now been tested in short-term studies on a small number of individuals that are carriers of the disease (i.e., family members with only one copy of the defective gene and no obvious clinical symptoms). These very recent preliminary studies suggest that kinetin levels achieved in people are sufficient to yield measurable changes in splicing of the FD gene in vivo.

We think that our current high-throughput screen may come up with compounds that are even more potent than kinetin. Our screening strategy involved testing most currently FDA-approved drugs. Therefore we may be able to move very quickly from the results in our iPS cell model to actually testing candidate compounds in patients.

On a larger scale, the success of our FD work has stimulated other scientists to use similar approaches for a broad range of human disorders. It will be important to see how often an iPS cell approach can capture a disease phenotype, teach us something truly new about a disease, or serve as an actual surrogate assay to perform in vitro drug discovery. There is considerable interest in major drug companies across the world to use similar approaches in their own drug discovery efforts.

The main problem currently is to define whether the contribution of iPS-based disease modeling is limited largely to early onset monogenic disorders such as FD, spinal muscular atrophy, Rett syndrome, or fragile X, or whether there will be similar success for the more common late-onset disorders with unknown or very complex genetic contribution.

SW: Do you foresee any social or political implications for your research?

There were a few issues that I did not necessarily foresee when we started our work. We started our research on FD from the outside without any financial support from the FD community. But we quickly realized the very strong opinions and controversies among the stakeholder families in this field. Given the fact that nearly all FD patients are of Ashkenazi-Jewish heritage, we got a particularly strong response from the Jewish community, and still today I get a visit nearly every month by a local Rabbi who asks about progress in our lab research on FD.

There were also unusual questions from reporters with potential social / political implications such as whether decreased incidence of FD due to extensive genetic screening of Ashkenazi Jewish communities will impact our work, questions that I typically do not face for any other projects (e.g., N. Engl. J. Med. 363: 1397-1409, 2010).

At a broader scope—beyond FD—iPS cell technology will likely have many interesting social and political implications. For example, some countries have started to think about banking iPS cells of the whole population. Such cell banks could be used in the future for personalized medicine to generate genetically matched replacement tissues or to test for individual response of each patient to a given drug regimen.

On a more Orwellian scope one could imagine that iPS cells in combination with whole genome sequencing may yield unprecedented information for each person. Such iPS cell lines could allow to actually "test-run" the individual genetic potential of a person for any organ, including the brain, in a manner similar to the ongoing disease modeling studies. While such ideas may still be "science fiction" today, they raise a number of social and political issues that may be worth considering ahead of time.End

Lorenz Studer
Member, Developmental Biology Program
Director, Sloan-Kettering Center for Stem Cell Biology
New York, NY, USA



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