Gene Therapy Improves Parkinson’s Symptoms

American scientists may have achieved a breakthrough in the treatment of Parkinson’s disease. The team utilized a gene-therapy technique to deliver a gene encoding the inhibitory GABA molecule to the overactive brain area (subthalamic nucleus) of a dozen of Parkinson’s patients. Motor function tests and PET scans, used for this purpose for the first time, showed that the treatment normalizes brain function and that the effects are still present a year later, with no side effects. The researchers believe this treatment offers hope to people suffering from Parkinson’s disease and other neurological diseases.
Dr. Michael Kaplittinjects gene-therapy virus into Nathan Klein (Credit: Weill Cornell Medical College) 
Dr. Michael Kaplitt injects
gene-therapy virus
into Nathan Klein (Credit: Weill
Cornell Medical College)

Parkinson’s disease is a neurodegenerative illness, which usually affects men and women over the age of 65. The illness is characterized by a steady loss in the brain cells that produce the neurotransmitter dopamine, which alters the function of brain networks controlling motor function. Medications and surgical techniques can treat some of the symptoms of the progressive disease, such as resting tremors, slowness of movement, and muscle stiffness, but there is no cure. 

Together with his colleagues, Michael Kaplitt, MD, Associate Professor of Neurological Surgery and Director of Movement Disorders Surgery at the New York-Presbyterian Hospital/Weill Cornell Medical Center, implemented a gene–therapy technique for the treatment of Parkinson’s disease. This technique utilizes an altered, harmless form of an adeno-associated virus (AAV) to deliver a gene of interest to the therapeutic site. In this case, the glutamic acid decarboxylase (GAD) gene was delivered into the subthalamic nucleus of the brains of Parkinson’s patients. This gene makes an inhibitory chemical called GABA, which decreases the activity in the subthalamic nucleus, a brain area that tends to be extremely overactive in Parkinson’s patients. 

This study, the first of its kind, was designed as a phase I safety study. To reduce risks and to better assess the treatment, the investigators injected the GAD-bearing AAV vector into the subthalamic nucleus on only one side of the patients’ brains. 

Andrew Feigin, MD, and David Eidelberg, MD, of The Feinstein Institute for Medical Research, who collaborated with Dr. Kaplitt, used a standard assessment of motor function, called the Unified Parkinson’s Disease Rating Scale (UPDRS), to identify changes in the patients’ symptoms over the next 12 months. In order to detect changes in brain activity, the patients underwent positron emission tomography (PET) scans before the surgery, and then twice after it- six months later and then again one year after the surgery. 

The clinical and neurological efficacy results were encouraging, as significant improvements in the UPDRS scores were observed in the ‘off-state’ phase (when Parkinson’s patients have been off their medicines for 12 hours) and also in the on-medication phase. The results from brain scans of the gene therapy patients supported the clinical outcome and revealed that the condition of the motor network on the untreated side of the body deteriorated, while that on the treated side improved and showed a more normal level of activity. The PET results also demonstrated that only the motor networks in the brain were altered by the therapy, whereas brain networks that affect cognition were not affected or harmed.  

The operating room theater (clockwise from left): Dr. Yu-Hung Kuo, Dr. Michael Kaplitt, Dr. Matthew During, and patient Nathan Klein (Weill Cornell Medical College) 
The operating room theater
(clockwise from left): Dr. Yu-Hung Kuo,
Dr. Michael Kaplitt, Dr. Matthew During,
and patient Nathan Klein
(Credit: Weill Cornell Medical College)

This phase 1 study has successfully achieved its primary objective of safety determination, as no adverse events related to the treatment and no immunological changes have been detected. The study also demonstrated the feasibility of PET scanning as a valuable marker in testing novel therapies for Parkinson’s disease. 

In order to determine whether improvements persist longer than a year following surgery, a longer follow-up is required. These initial results have to be validated in a longer, larger trial, hence the scientists are now designing a phase 2 blinded study that would include a larger number of patients and test the efficacy of the treatment. 

“We believe that this breakthrough trial has implications that go far beyond Parkinson’s research,” Dr. Kaplitt says. “It’s taken us nearly two decades of hard work to get here, but the success of this trial lays the foundation for the use of gene therapy against neurological diseases generally”. 

Other experimental techniques for treatment of neurodegenerative disorders previously reported by TFOT include stem cells transplants and upregulation of a molecule that prevents neurodegeneration

Press releases announcing the gene therapy breakthrough can be found on the Weill Cornell Medical College Neurological Surgery webpage and on the Feinstein Institute for Medical Research at North Shore-Long Island Jewish Health System webpage

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