Early Translational I
ICOC Funds Committed:
Parkinson’s disease is a debilitating, neurological disorder that affects over one million Americans. An additional 50,000 Americans get the disease every year. It tends to affect patients over 55 years. However, younger patients of 30-40 years old can also get the disease. Patients lose the ability to control their movement. Their muscles become rigid, the arms shake, and the patient tends to walk in a shuffling manner. Everyday skills like eating, tying shoe laces and buttoning shirts become difficult to perform, and the quality of life deteriorates. Scientists believe that the main cause of the disease is death of nerve cells in the brain that make the neurotransmitter dopamine. When dopaminergic (DAergic) neurons die, the level of brain dopamine is reduced. Doctors treat the disease by replacing the lost brain dopamine using two drugs: 1) L-DOPA, that is made into dopamine in the brain, and 2) Dopamine-like drugs, e.g. pramipexole, that mimic the action of dopamine. However, these drugs treat the symptoms of the disease, not the cause. DAergic neurons continue to die, even though the patient might feel better. Eventually, after 5-7 years of treatment, the drugs don’t work as well. Scientists believe that an alternative method of treating the disease is to replace the dead DAergic neurons with live DAergic neurons made in the laboratory, and transplanted into the brain by a procedure called cell therapy. There is hope in the scientific community that DAergic neurons needed to treat Parkinson’s disease can be made from stem cells, and this research is supported by the California Institute of Regenerative Medicine. However, making DAergic neurons from stem cells on a large scale will likely to take many years. An alternative approach is to use a type of cell called a DAergic progenitor neuron. Unlike stem cells that can make all of the different types of cells in the body, committed progenitors make only the one type of cell they are committed to make, in this case, DAergic neurons, and in limited quantities, compared with stem cells. There are one million DAergic neurons in the region of the brain associated with Parkinson’s disease. These neurons can be removed from the human fetal brain, and grown in the laboratory to produce five million, that can be used to treat five patients. Growing the cells is just one of many steps needed for success. The DAergic neurons must be detached from the growing surface, dispersed, separated from dead cells, packaged into small clusters of 5-50 cells, and maintained in a viable state at room temperature for up to 24 hours. They must also be treated with a neuroprotective agent to minimize cell death after transplantation into the brain. Lastly, the cells will be tested in an animal model of Parkinson’s disease, and then in a clinical trial. One advantage of this approach is that it will save valuable time, by preparing the way for the use of DAergic neurons produced from stem cells.
Statement of Benefit to California:
The estimated cost to the United States per year for drugs to treat Parkinson’s disease (PD) is $1.5 B. California has 10% of the population of the United States, so the pro-rated cost to California is $150,000,000. The estimated cost to the economy of the United States per year due to lost productivity and the cost of care related to PD is $5.6 B. On a pro-rated scale, the cost to California is $560,000,000. Anyone who has witnessed human beings with PD in group therapy will know that the human cost of this debilitating disease is difficult to describe. It is seen in the eyes of a proud middle aged woman who reaches for a hand shake, but is defeated and humiliated by the imposed slowness of her movement. There is the businessman who uses his left hand to physically constrain the violent shakes of his right hand during meetings. Since 1961, scientists have understood that the major cause of PD is the degeneration of Dopaminergic (DAergic) neurons in the substantia nigra (SNc) in the ventral midbrain. Symptoms appear when 70-80% of our DAergic neurons have degenerated. Drug therapy is very successful in relieving symptoms, and improving the quality of life for patients. However, drugs do not modify the underlying neuropathology of the disease. The disease continues to progress, even as the patient’s symptoms are relieved. As the disease progresses, drugs become less effective, and the disease becomes difficult to treat in this chronic stage. The first study to suggest that cell therapy might be an effective treatment for PD was published by Mark Perlow at the National Institutes of Health in 1979. Since then, over 200 patients have been transplanted with DAergic neurons derived from human fetal brain tissue. This effort culminated with a clinical trial that was published by Olanow et al in 2003. The results were negative. We have also learnt that the transplanted DAergic neurons can also degenerate exactly like the patient’s original DAergic neurons. Two conclusions follow from these results: 1) Transplantation of human, fetal nigral tissue into the brains of PD patients is not an effective treatment for PD. 2) When DAergic neurons are introduced into the brains of patients, they must be protected, or they will also degenerate. DAergic neurons for use in cell therapy to treat PD must be prepared in the laboratory as a nearly pure population of DAergic neurons from stem cells ultimately, and progenitors in the short term. We must also discover new drugs to protect the DA neurons after transplantation. This grant application addresses both of these issues. We have developed a patented method for preparing DAergic neurons in the laboratory, and then optimizing them for transplantation. We are also actively working on new drugs to protect DAergic neurons after transplantation. Our first drug candidate called [REDACTED] is being moved forward for testing in the clinic. Cell therapy has the potential to slow down the progression of PD