Dopaminergic neurons and proliferation-competent precursor cells for treating Parkinson's disease

Abstract

This disclosure provides improved methods for obtaining populations of neural progenitor cells and differentiated neurons from pluripotent stem cells. The technology can be used to produce progenitors that proliferate through at least 40 doublings, while maintaining the ability to differentiate into a variety of different neural phenotypes. Cell populations have been obtained that contain a high proportion of cells staining for tyrosine hydroxylase, which is a feature of dopaminergic neurons. The neural progenitors and terminally differentiated neurons of this invention can be generated in large quantities for use in drug screening and the treatment of clinically important neurological disorders, such as Parkinson's disease.

Description

BACKGROUND New research into the derivation and expansion of cell lines suitable for human administration promises to usher in a brave new world medical care. Devastating and previously intractable disease conditions may yield to the promise of regenerative medicine, providing that science continues to benefit from important new discoveries in the cell biology of neurons and neural precursor cells. Amongst the disease conditions in need of a clinical advance are those relating to neurological dysfunction. Near the top of the list is Parkinson's disease, an idiopathic, slowly progressive, degenerative disorder of the central nervous system, characterized by slow and decreased movement, muscular rigidity, resting tremor, and postural instability. The symptoms ensue from progressive deterioration of pigmented neurons in the substantia nigra, locus caeruleus, and other brain stem dopaminergic cells, causing a depletion of the neurotransmifter dopamine. Parkinson's disease is the fourt...

AI Technical Summary

Benefits of technology

In one embodiment of the invention, neural cells are made from human pluripotent cells differentiated as described into neuronal precursor cells, and then passaged in culture. Using embryonic stem cells as the originating cell type facilitates generation of a rapidly expanding population that nonetheless maintains full capacity to undergo terminal differentiation into functioning neurons—either when cultured with neurotrophins in the absence of mitogens, or when administered to a suitable subject. Depending on the conditions used, precursor populations can be generated that have the capacity to differentiate into a high proportion of tyrosine hydroxylase positive cells. This phenotype is consistent with dopaminergic neurons, desirable for treatment of Parkinson's disease.

Problems solved by technology

Regardless of the age of presentation, the disease often has devastating consequences for those afflicted.

What makes afflictions of the nervous system so difficult to manage is the irreversibility of the damage often sustained.

But there is a severe shortage of suitable tissue.

Unfortunately, it has not been shown that progenitors isolated from neural tissue have sufficient replicative capacity to produce the number of cells necessary for human clinical therapy.

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