Huntington’s disease is an inherited brain disorder that causes progressive uncontrolled movements, dementia and culminates in death. The symptoms of Huntington’s disease are involuntary jerking or writhing movements (chorea), involuntary, sustained contraction of muscles (dystonia), muscle rigidity, slow, uncoordinated fine movements, slow or abnormal eye movements, impaired gait, posture and balance, difficulty with the physical production of speech, and difficulty swallowing.
More than a quarter of a million Americans are affected by Huntington’s disease. Huntington’s disease is passed through families even if only one parent has the abnormal huntingtin gene, since it is inherited as an autosomal dominant. The huntingtin gene is found on the fourth chromosome, and Huntington’s disease-causing mutations result from the expansion of a trinucleotide (CAG) repeat (Jones L, Hughes A. Int Rev Neurobiol.2011;98:373-418 & Reiner A, Dragatsis I, Dietrich P. Int Rev Neurobiol. 2011;98:325-72). This trinucleotide repeat is normally repeated up to 28 times on the chromosome, but polymerase slip during DNA replication can expand the number of these repeats so that an abnormal form of the Huntingtin protein to be made. The abnormal Huntingtin protein accumulates in the brain and this cause the disease’s devastating progression. Individuals usually develop symptoms in middle age if there are more than 35 copies of the CAG repeats. A more rare form of the disease occurs in youth when the number of CAG repeats occurs many more times.
Huntington’s disease can be managed with medications. For example Terabenazine (Xenazine) suppresses the involuntary jerking and writhing movements associated with Huntington’s diseases. Antipsychotic drugs such as Haloperidol (Haldol) and Clozapine (Clozaril) can suppress movements but they can also increase muscle rigidity and involuntary contractions. Other medications like clonazepam (Klonopin) and diazepam (Valium) can suppress the chorea, dystonia and muscle rigidity.
Even though brain grafts in laboratory animals have shown some promise, these experiments used a chemically induced form of Huntington’s disease. Because the surrounding tissue was genetically normal, implanted brain tissue simply integrated into the damaged brain tissue and healed it. However, clinical Huntington’s disease is due to mutations in the huntingtingene, and the surrounding brain tissue is not genetically normal. Therefore grafted stem cells are killed off by the toxic environment in the brain (Clelland CD, Barker RA, Watts C. Neurosurg Focus.2008;24(3-4):E9 & Dunnett SB, Rosser AE. Exp Neurol. 2007 Feb;203(2):279-92). To overcome this problem, researchers have developed a technique for that used stem cells to deliver therapeutic agents that specifically target the genetic abnormality found in Huntington’s disease.
Scientists at the UC Davis Institute for Regenerative Cures have developed a novel, and promising approach that might prevent the disease from advancing. Jan A. Nolta, principal investigator of the study and director of the UC Davis stem cell program and the UC Davis Institute for Regenerative Cures, thinks that the best chance to halt the disease’s progression will be to reduce or eliminate the mutant Huntingtin (Htt) protein found in the neurons of those with the disease. RNA interference (RNAi) technology has been shown to be highly effective at reducing Htt protein levels and reversing disease symptoms in mouse models.
Nolta said: “For the first time, we have been able to successfully deliver inhibitory RNA sequences from stem cells directly into neurons, significantly decreasing the synthesis of the abnormal Huntingtin protein. Our team has made a breakthrough that gives families affected by this disease hope that genetic therapy may one day become a reality.” She continued: “Our challenge with RNA interference technology is to figure out how to deliver it into the human brain in a sustained, safe and effective manner,” said Nolta. “We’re exploring how to use human stem cells to create RNAi production factories within the brain.”
The research team from UC Davis showed for the first time that inhibitory RNA sequences are directly transferable from donor cells into target cells to greatly reduce unwanted protein synthesis from the mutant huntingtin gene. To transfer these inhibitory RNA sequences into their targets, Nolta’s team genetically engineered mesenchymal stem cells (MSCs) from bone marrow that had been collected from unaffected human donors. Over the past two decades, Nolta and her colleagues have shown MSCs are safe and effective vehicles for the transfer of enzymes and proteins to other cells. According to Nolta, MSCs can also transfer RNA molecules directly from cell to cell, in amounts sufficient to reduce levels of a mutant protein by over 50% in the target cells. This discovery has never been reported before and offers great promise for a variety of disorders.
Nolta has recently received a Transformative Research Grant from the National Institutes of Health (NIH) to study how MSCs can transfer microRNA and other factors into the cells of damaged tissues, and how that process can be harnessed to treat injuries and disease. Nolta said: “Not only is finding new treatments for Huntington’s disease a worthwhile pursuit on its own, but the lessons we are learning are applicable to developing new therapies for other genetic disorders that involve excessive protein development and the need to reduce it. We have high hopes that these techniques may also be utilized in the fight against some forms of amyotrophic lateral sclerosis (Lou Gehrig’s disease) as well as Parkinson’s and other conditions.”
Published – Scott D. Olson, Jan Nolta et al.; Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington’s disease affected neuronal cells for reduction of huntingtin;” Molecular and Cellular Neuroscience,2011; DOI: 10.1016/j.mcn.2011.12.001.