Successful Phase I Gene Therapy Trial with PD patients

HD Lighthouse Contributing Editor's Comment: Neurologix has announced the results of a Phase I gene therapy trial with twelve Parkinson's Disease patients.

A gene called glutamic acid decarboxylase (GAD) was injected into the brain and delivered to the subthalamic nucleus using an adeno-associated virus (AAV) vector. Viruses typically invade cells and insert their own genes. This technology involves removing the virus's disease genes and inserting a therapeutic gene to be delivered instead. In this trial, the GAD gene was chosen because it produces the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). GABA will reduce the overactivity of the neurons in the the subthalamic nucleus.

This was a phase I study which means that the researchers were looking to see if the procedure was safe and well tolerated. As hoped, the patients continue to do fine one year after the surgery. What's exciting about the study, however, is that there were statistically significant results even with such a small sample. Not only did brain metabolism improve, as measured by a PET scan, but the patients showed clinical improvement on the UPDRS which measures disease progression. These results are also remarkable because only one side of the brain was treated in this part of the study.

These results are of interest to the HD community because this is the first gene therapy with neurological patients. The method of delivery was clearly effective and appears to be safe. Neurologix is also researching gene therapy in Huntington's Disease using the XIAP gene which inhibits apoptosis (programmed cell death), one of the HD pathologies. They have had success in a rat model of Huntington's Disease. Another area of investigation is the use of neurotrophic factors for neuroprotection and regeneration, another promising approach for Huntington's Disease. The press release for the PD study and the HD study are below.

References:

J. Luo, M. Kaplitt, H. Fitzsimons, D. Zurga, Y. Liu, M. Oshinksky, M. During. Subthalamic GAD gene therapy in a Parkinson's Disease rat model. Science. Vol. 298 October 12, 2002

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 18 Oct 2006

FORT LEE, N.J., Oct. 17 /PRNewswire-FirstCall/ -- Neurologix, Inc. (OTC Bulletin Board: NRGX), a biotech company engaged in the development of innovative gene therapies for disorders affecting the brain and central nervous system, announced today that it has successfully completed its landmark Phase I trial of gene therapy for Parkinson's disease with statistically significant results. The data was presented at the 36th Annual Meeting of the Society of Neuroscience in Atlanta.

In a presentation entitled "Subthalamic GAD gene transfer improves brain metabolism associated with clinical recovery in Parkinson's disease," Matthew J. During, MD, D.Sc. presented findings of the open label, dose escalating, unilateral trial, which confirmed the safety and tolerability in all 12 patients studied out to one year. Though efficacy was only designated as a secondary outcome, the trial also yielded statistically significant clinical efficacy and neuro-imaging results.

At one year, all 12 patients as a group demonstrated a clinical improvement of 25% in the Unified Parkinson's Disease Rating Scale (UPDRS) compared to baseline (p < 0.005). Nine of the 12 patients showed an average improvement of 37%, and five of these patients had substantial improvement of between 40% and 65%. "This gene therapy trial is particularly unique and the clinical data unusually promising because the treatment was confined to just one side of the brain," stated Dr. During. In its next trial, the Company plans to infuse its treatment into both sides of the brain.

Clinical improvement also correlated well to metabolic brain changes as measured by Positron Emission Tomography (PET) scan. PET is an imaging method that measures brain metabolism following the injection of a radioactive analog of glucose (fluorodeoxyglucose). The PET scan data revealed a significant improvement (p < 0.001) in brain metabolism on the treated side of the brain as compared to the untreated side.

About the Study:

The Phase I trial was performed at New York-Presbyterian Hospital/Weill Cornell Medical Center by Michael G. Kaplitt, MD, Ph.D. and Dr. During, both co-founders of the Company. Drs. Kaplitt and During have collaborated in research in this field for more than 10 years. All patients were evaluated neurologically and by PET scan by Drs. Andrew Feigin and David Eidelberg at North Shore University Hospital.

This was a 12-patient study with four patients in each of three dose escalating cohorts. All procedures were performed under local anesthesia and all 12 patients were discharged from the hospital within 48 hours of the procedure and followed for 12 months. Primary outcomes of the study design, safety and tolerability, were successfully met. There were no adverse events reported relating to the treatment.

The gene transfer procedure utilized the AAV (adeno-associated virus) vector, a virus that has been used safely in a variety of clinical gene therapy trials and the vehicle that will be used in all of the Company's first generation products, including epilepsy and Huntington's disease. In its Parkinson's disease trial, Neurologix used its proprietary AAV-GAD gene transfer technology ("NLX").

"The Company is very excited about the results of this trial. We look forward to further validating these results in the next trial and continuing our efforts to develop a significant new treatment for Parkinson's disease worldwide," stated Neurologix Chief Executive Officer and President John E. Mordock.

The Annual Meeting of the Society of Neuroscience attracts more than 30,000 clinicians and scientists gathered from around the world to exchange ideas about cutting-edge research on the brain, spinal cord, and nervous system in science's fastest growing field, Neuroscience.

Neurologix's initial development efforts are focused on their core gene therapy technology, NLX, for treating Parkinson's disease, epilepsy and Huntington's disease. Neurologix is located in Fort Lee, NJ. More information about the Company can be found on its website, www.neurologix.net.

Neurologix Pre-Clinical Results Show Potential for Gene Therapy Treatment of Huntington's Disease

FORT LEE, N.J., Nov 18, 2005 (BUSINESS WIRE) -- Neurologix, Inc. (OTCBB: NRGX) today announced findings from preclinical studies, which showed that the gene XIAP (X-linked inhibitor of apoptosis) may prevent the progression of Huntington's disease. Neurologix scientists demonstrated that a mutated form of the gene delivered by an adeno-associated virus (AAV) vector, introduced using standard neurosurgical techniques can improve motor deficits associated with the disease. Huntington's disease is a fatal neurological genetic disorder characterized by debilitating movement abnormalities, for which there is currently no effective treatment available. The findings were presented in a poster session during the 35th Annual Meeting of the Society for Neuroscience in Washington D.C. by Sergei A. Musatov, Susan E. Browne, Matthew S. Henning, Mihaela A. Stavarache, Joshua A. Goldfein, and Michael G. Kaplitt. The title of the poster was "Neuroprotective effects of XIAP in models of Huntington's disease."

Using cell culture models of the disease, the researchers showed that a truncated form of XIAP lacking the RING domain (RING) may significantly reduce cell death caused by a mutated form of human huntingtin gene.

The researchers further investigated the neuroprotective effects of dXIAP in a transgenic animal model by injecting presymptomatic mice with AAV vectors encoding dXIAP into the striatum, an area of the brain largely affected in Huntington's patients. In the study, mice injected with this vector experienced significant protection from motor dysfunction when compared to mice treated with a control vector. dXIAP also appeared to prolong the life-span of the mice by 16%. Furthermore, no adverse effects due to dXIAP over-production were observed.

"These preclinical data in the Huntington's disease study show the potential of the Company's neuroprotection approach of using AAV vectors to deliver therapeutic genes for the treatment of serious and debilitating neurological disorders," stated Michael Sorell, Chief Executive Officer. "These studies and studies on additional compounds will need to be confirmed and the mechanisms and limitations further elucidated before testing in humans can begin," he added.

Source: Neurologix

printer friendly version

	Read the HDAC/HDLighthouse Forum. Post your comments