Gene Therapy Injected into the Brains’ of Mice with Huntington’s Disease

Huntington's disease is a inheritable single-gene disorder. Onset of Huntington’s usually occurs in the 4th decade. The prognosis for the disease is progressive disability, with death occurring 10-12 years from the onset of the symptoms. You can find some useful information about Huntington's Disease at the Your Genes, Your Health website and Harvard's Centre for Neurodegeneration & Repair website. The latter website has the following passage which captures how tragic the disease is:

Huntington's disease was no stranger to Leonore Wexler. As a girl, she watched it afflict her father and brothers, taking over their minds and bodies before killing them by middle age. Somehow, she thought, she had escaped the disease. One day, however, Leonore's daughter Nancy noticed that her mother was changing. Nancy describes,

"Now she seemed completely overwhelmed by everything. … I noticed that her feet seemed to be constantly moving and she seemed almost sylphlike and disappearing before my eyes. … Later that year, while my mother was on jury duty in Los Angeles, a policeman accused her of being drunk at 8:30 in the morning. This really devastated her, for she knew what it meant. … I suddenly learned that my mother was dying, and that my sister … and I each had a one in two chance of getting Huntington's.”

From "Prognostications and Predispositions” by Nancy Wexler, Annals of the New York Academy of Sciences 882:22-31 (1999)

This story in Pharmalive is encouraging as it notes that researchers (at Rush University Medical Center, Chicago, and Ceregene Inc., San Diego) have successfully used gene therapy to preserve motor function and stop the anatomic, cellular changes that occur in the brains of mice with Huntington’s disease. Here are some snippets from the story:

Researchers used a defective virus, adenoassociated viral vector, (AAV) to deliver gene therapy, glial-derived neurotrophic factor (GDNF), directly to the brain cells of mice.

....Three groups of mice were involved in the 4 month study. All mice were modeled to have the genetics of HD. The HD mice exhibited symptoms of motor deficits including loss of control, gait abnormalities, hypokinesia (abnormally decreased mobility and motor function), hind limb clasping behaviors and muscle weakness. One control group of mice did not receive any gene therapy. A second control group was injected with a placebo gene therapy. The third group received the active GDNF gene therapy.

To measure fine motor coordination, balance and fatigue, researchers evaluated mice walking on a rotating rod. Mice injected with the gene therapy performed significantly better than the other mice. These mice also showed diminished hind limb clasping (a simulation of motor control behavior in HD patients). Perhaps most importantly, gene delivery of GDNF provided neuroprotection in the brain, with reduced density of brain inclusions and less cell death.

....Kordower says the study suggests a new approach to forestall disease progression in newly diagnosed HD patients by delivering potent trophic factors with effects that are long-term and non-toxic. "If these results can be replicated in HD patients, it would represent a significant advance in the treatment of this tragic disease," agreed Dr. Jeffrey Ostrove, President and CEO of Ceregene.

The study is published in the June 13th issue of the Proceedings of the National Academy of Sciences of the United States of America and you can download the paper from here (subscription needed). Here is the abstract of the published article:

Huntington’s disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.

Cheers,
Colin