Huntington Disease therapy fails

Huntington Disease in a fatal, inherited disease that causes degeneration of the central nervous system. It clinically manifests itself as severe movement and cognitive problems, and the patient gradually loses control of their body in a slow, painful slide to death that is difficult to watch.

A treatment for Huntington Disease that generated a far amount of hope in the 1990s was to transplant healthy neural tissue from fetuses. In particular, the striatum — the brain region most severely affected in Huntington disease was replaced by fetal neural tissue. Unfortunately, this tissue came from babies who were killed by selective abortion. Unfortunately, clinical follow-up of this approach has shown that technique does not work (Cicchetti, F. et al. Proc. Natl Acad. Sci. USA advance online publication doi:10.1073/pnas.0904239106 (2009).


University of South Florida neurosurgeon Thomas Freeman and his colleagues have conducted a post-mortem analysis of the brains of three people with Huntington’s disease who received fetal striatal-tissue transplants a decade before they died. The results were rather clear – instead of slowing or stopping the progression of the disease, the grafts degenerated even more severely than the patients’ own tissue.

Early results for this procedure generated some hope.  Animal experiment in rats (Kendall, A. L. et al. Nature Med. 4, 727-729 (1998) and non-human primates (Isacson, O. et al. Nature Med. 1, 1189-1194 (1995) showed that transplanted tissue could replace lost striatal neurons and improve behavioural symptoms.  Also, early clinical results tended to support the efficacy of this technique.  Patients who had received these striatial grafts showed modest improvements and autopsies showed that the grafts of fetal neural tissue had survived and integrated into the brain (see Hauser, R. A. et al. Neurology 58, 687-695 (2002), and Bachoud-Lévi, A.-C. et al. Lancet Neurol. 5, 303-309).

Unfortunately, this more recent examination shows that the animal models were deceptive.  The animals were treated with chemicals that destroyed the striatum but left the rest of the brain intact.  In the case of human patients, the entire brain is diseased, and dying neurons release extensive amounts of neurotransmitters that kill neurons by overdosing them on these neurotransmitters.  The transplanted tissue is killed by neurotransmitter overdose.

This has implications for stem cell treatments of Huntington Disease.  Transplanted stem cells or neural progenitor cells will be subjected to this same cocktail of death.  Therefore another strategy is needed.

Fortunately, some cells can surround transplanted cells and protect them from death by neurotransmitter overdose.  For example, co-transplantation of testicular Sertoli cells with neural grafts not only produce an area of localized immuno-suppression (due to local secretion of GDNF by the Sertoli cells) but they can push stem cells into dopaminergic neurons, which are killed in Parkinson Disease (see Halberstadt C, Emerich DF, Gores P. Expert Opin Biol Ther. 4, (2004): 813-25).  Therefore, some new thinking on this front might provide a new treatment scheme.


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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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