Cell-based therapies for Parkinson's disease: past, present, and future

Abstract

Parkinson's disease (PD) researchers have pioneered the use of cell-based therapies (CBTs) in the central nervous system. CBTs for PD were originally envisioned as a way to replace the dopaminergic nigral neurons lost with the disease. Several sources of catecholaminergic cells, including autografts of adrenal medulla and allografts or xenografts of mesencephalic fetal tissue, were successfully assessed in animal models, but their clinical translation has yielded poor results and much controversy. Recent breakthroughs on cell biology are helping to develop novel cell lines that could be used for regenerative medicine. Their future successful clinical application depends on identifying and solving the problems encountered in previous CBTs trials. In this review, we critically analyze past CBTs' clinical translation, the impact of the host in graft survival, and the role of preclinical studies and emerging new cell lines. We propose that the prediction of clinical results from preclinical studies requires experimental designs that allow blind data acquisition and statistical analysis, assessment of the therapy in models that parallel clinical conditions, looking for sources of complications or side effects, and limiting optimism bias when reporting outcomes.

FIG. 1.

Areas of the central and peripheral nervous system presenting pathology in PD.

FIG. 2.

Timeline of major events shaping the development of CBTs for PD. Refer to text for a more comprehensive list.

FIG. 3.

Ex vivo gene therapy using human neuroprogenitor cells. hNP cells were transfected with lentiviral vectors encoding for glial derived neurotrophic factor (GDNF) and transplanted into the striatum of a cynomolgus monkey intoxicated with a single intracarotid artery injection of MPTP. Used with permission from ref. .

FIG. 4.

Sources of cells for PD CBTs.

FIG. 5.

Possible applications of cell-based technologies for PD. CBTs for PD are traditionally envisioned as cell replacement strategies aiming for circuit restoration. New developments in gene transfer, stem cells, and tissue culture techniques are expanding CBTs' role in vivo as a mean for localized delivery of therapeutic molecules that can be spontaneously secreted or genetically engineered to be produced. In vitro, cell cultures are proposed as tools to help understand PD, develop and screen new therapies.

FIG. 6.

Immunological reaction to intracerebral injections. CD68 expression (marker for microglia/macrophages; arrows) is observed after MRI-guided stereotaxic intracerebral injections of: (A) Vehicle (cell culture media), (B) hNP cell transplants.

FIG. 7.

Methods of labeling and identification of human cells grafted into the brain of nonhuman primates (A) Immunohistochemistry against bromodeoxyuridine (BrdU). hNP cells were incubated with BrdU before transplantation into the striatum of a cynomolgus monkey (used with permission from ref. 112). (B) hNP cells from a male donor were transplanted in a female cynomolgus monkey host brain and identified using a probe against the Y chromosome (pink dots) (used with permission from ref. 42). (C) immunohistochemistry against Green Fluorescent Protein (GFP)–labeled hES cells transplanted into the striatum of a rhesus monkey.

FIG. 8.

The microenvironment of the PD brain for host and transplanted cells.