Autologous Induced Pluripotent Stem Cell-Derived Neurons to Treat Parkinson's Disease

In 2012, we planned a program to develop a neuron replacement therapy for Parkinson's disease (PD) that would have the greatest promise to help the patients. PD is a movement disorder caused by the progressive, inevitable loss of a specific type of dopamine neuron in the brain. The only viable treatment to reverse the progress of the disease is to replace those neurons; we decided to make dopamine neurons that matched the patients, by differentiating induced pluripotent stem cells (iPSCs) that we generated from individuals with PD. This autologous cell therapy is entering the regulatory approval process this year with the U.S. Food and Drug Administration to begin to transplant the cells in the following 1 to 2 years.

The idea of using pluripotent stem cells (PSCs) for dopamine neuron replacement therapy arose in the scientific community as soon as the first human pluripotent stem cells (hPSCs), embryonic stem cells (hESCs), were derived 20 years ago. This idea did not require a great deal of imagination; scientists had already shown, starting in the 1980s, that transplantation of fetal brain tissue containing the precursors of dopamine neurons could, in some cases, reverse the symptoms of PD.

The fetal transplant work was bold and groundbreaking, but it had complicating issues: dopamine neuron-containing brain tissue had to be dissected from very young aborted fetuses that are difficult to obtain and of uncertain quality, and abortion, especially in the United States, is a very controversial issue. In addition, some of the transplanted patients developed uncontrolled jerky movements, graft-induced dyskinesias, which, it was later learned to be caused by the presence of other neuron types that arose from the complex fetal tissue.

Optimistic scientists thought that hPSCs could be differentiated in culture into the specific type of dopamine neuron lost in PD. This would enable production of safe effective neurons and enable the treatment a large number of people with PD [1].

This idea was buoyed by the policy change introduced by President G.W. Bush in 2001 that allowed the NIH to fund hESC research for the first time, using a limited set of already established hESC lines. This sparked interest in the potential of hESCs for human therapy, which led to the birth of state-sponsored funding agencies dedicated to hESC research, most notably in 2004 in California (California Institute for Regenerative Medicine) and in New York (New York Stem Cell Science, NYSTEM).

Thanks to this U.S. states' support and investment by the European Union and Japan in their own countries, four programs have emerged that are planning clinical trials in the next few years using dopamine neurons derived from PSCs for use in neuron replacement therapy for PD [2].

Although their goals for clinical use of the neurons are very similar, the starting materials for making those neurons are different for the four programs. Two of these programs, in the European and in New York State, are each using different established hESC lines. The group in Japan plans to use a single line of iPSCs, which are identical in developmental potential to hESCs, but are made from human skin cells by reprogramming technology developed 10 years ago.

The fourth group, in our laboratory in California, is different from the others in one important aspect: it is a personalized therapy, in which we generate iPSCs from each patient and will transplant immunologically matched neurons. This means that there are no costs or potential side effects from giving the patients immunosuppressive drugs.

A question I often hear is, if using a patient's own cells will avoid immunosuppression, why would anyone use unmatched hESCs or iPSCs? The answer lies in history, science, and economics.

The historical reason is simple: hESCs were the only PSCs available before widespread adoption of improved iPSC technologies, especially nonintegrating reprogramming methods, so projects launched before about 2012 were necessarily or logically based on hESCs.

While the choice of hESCs is fixed in history, the scientific and economic issues in use of iPSCs are more fluid. Most of the scientific issues have already been solved by research that has taken place in the last 5 years. iPSCs have been shown to be functionally identical to hESCs, and a fear that reprogramming cells to iPSCs would lead to mutations has been overcome by results of whole-genome sequencing studies [3].

Since autologous transplantation requires an iPSC line from every patient, it has been necessary to develop improvements in differentiation protocols that were originally designed for a single hESC line. We now have methods that reliably produce high-quality dopamine neurons from iPSCs from every patient. We have also introduced genomics-based quality control assessments to ensure the consistent quality and genomic integrity of transplant-ready cultured cells.

The concerns about the economic issues associated with personalized therapy have diminished with the success of immunotherapy (CAR-T) for cancer. These therapies are currently custom designed using cancer patients' own T cells. The great upfront cost, several hundred thousand dollars for production of modified T cells from each patient, is mitigated by the fact that it is often effectively a cure for previously incurable cancers, and that there are no further costs for cancer therapy in those patients who recover.

We hope to begin a clinical trial by the end of next year, 2019, and our current efforts are focused on producing data for regulatory agencies that will assure them of the safety and efficacy of the autologous dopamine neurons. We have made iPSCs from each of the 10 patients in the initial trial and developed strict release criteria for the cells used for transplantation. We expect the cost of treating each patient to be high, but no higher than current CAR-T therapies, and as immunosuppression will not be required, the costs of posttransplant care will be far less than for the unmatched cell approaches. If we are successful, the restoration of health to people living with PD will be priceless.