The study by scientists from Laval University and USF has implications for the development of future cell therapies for Parkinson’s and Huntington’s disease

July 20, 2009 — Results of a new study published online this week in the Proceedings of the National Academy of Sciences question the long-term effects of transplanted cells in the brains of patients suffering from Huntington’s disease. The study, conducted by Dr. Francesca Cicchetti of Laval University in Québec, Canada, Dr. Thomas B. Freeman of the University of South Florida (USF) Department of Neurosurgery and Brain Repair, Tampa, FL, and colleagues provides the first demonstration that transplanted cells fail to offer a long-term replacement for degenerating neurons in patients with Huntington’s disease.

Huntington’s disease is a neurodegenerative disease of genetic origin that targets a particular type of neuron. The loss of these neurons is responsible for the appearance of involuntary movements as well as cognitive and psychiatric impairments. Over a decade ago, USF neurosurgeon Dr. Freeman initiated a clinical trial of neural cell transplantation in patients with Huntington’s disease in an attempt to alleviate the devastating symptoms that characterize this disease.

Some patients demonstrated some mild, transient clinical benefits that lasted for about two years. However, the loss of functional recovery after this time indicated that graft survival and functionality may be jeopardized long-term.

Study senior co-author Dr. Thomas Freeman, a professor in the USF Department of Neurosurgery and Brain Repair, is a leader in stem cell transplantation research for neurodegenerative disorders.

The post-mortem study of three cases described in PNAS is the first demonstration that 1) graft survival is indeed attenuated long-term, 2) the grafts undergo degeneration that resembles the pathology observed in Huntington’s disease, and 3) the brain’s inflammatory response could contribute to the compromised survival of grafted cells. The authors also demonstrated that cortical neurons develop Huntington’s disease synapse on the grafts, and may cause neurotoxicity to the healthy cells, inducing grafted neuronal cell death.

Last year, researchers at Rush University Medical Center, USF, and Mount Sinai School of Medicine published research in Nature Medicine showing that grafts in patients with Parkinson’s disease develop Lewy bodies — a marker of Parkinson’s disease — after 14 years. Those patients benefited from the grafts for about 12 years, and only about 5 to 8 percent of the transplanted cells had this finding.

“This latest study shows that grafts in patients with Huntington’s disease also undergo disease-specific neuronal degeneration,” said USF’s Dr. Freeman, a senior co-author of the study. “However, the neural degeneration in the (genetically unrelated) grafts was even more severe than what was observed in the patient’s own brain. Additionally, clinical benefit, if any, only lasted about two years. These findings may be important to future therapeutic trials of stem cells for the treatment of Parkinson’s and Huntington’s diseases.”

Despite the excitement for cell transplantation therapy using embryonic or stem cells, these results raise concerns for the therapeutic potential of transplantation as a treatment option for Huntington’s disease, the study authors report. However, these observations suggest new potential mechanisms involved in the development of the disease, they conclude. A more in-depth investigation could allow the development of novel therapeutic strategies. The control of the patient’s immune and inflammatory responses holds therapeutic potential and Dr. Cicchetti and colleagues continue their research in that direction.

Dr. Francesca Cicchetti is a professor at the Department of Psychiatry/Neuroscience at Laval University and a researcher in neurobiology. She directs a research laboratory, which focuses on the understanding of neuronal degeneration and the development of treatment strategies for neurodegenerative diseases.

Dr. Thomas B. Freeman is a USF neurosurgeon at Tampa General Hospital, and director of clinical research and medical director of the Center of Excellence for Aging and Brain Repair at the University of South Florida.

This work includes the scientific contribution of the following authors: Samuel Saporta (USF Department of Neurosurgery and Brain Repair), Robert Hauser (Parkinson’s Disease and Movement Disorders National Parkinson’s Foundation Center of Excellence, USF), Martin Parent (Groupe de recherche sur le système nerveux central (GRSNC)), Martine Saint-Pierre (Centre de Recherche du CHUL (CHUQ)), Paul Sanberg (USF Department of Neurosurgery and Brain Repair), Xiao Li (Emory University School of Medicine), John Parker (University of Louisville Health Sciences Center), Yaping Chu (Rush University Medical Center), Elliot Mufson (Rush University Medical Center), and Jeffrey Kordower (Rush University Medical Center).