Thursday, June 21, 2007

Dr. Michael Kaplitt's Viral DNA Gene Therapy for Parkinsons

Dr. Michael Kaplitt, a relatively young physician, leads a small new firm called Neurologix. The notable very preliminary result of the firm, is what seems to be very promising results from early stage testing of a means to attempt to inhibit the destructive effects of Parkinsons disease.

Here is a link to the article recently published in Lancet
An interview with a physician interpreting the preliminary results by Neurologix

Kaplitt's work is a novel effort to use a genetically modified virus as the vector to introduce modified DNA to afflicted brain tissues, in a manner that reverses a fundamental mechanism of Parkinsons disease, a deficit of GABA gamma-aminobutyric acid, the major inhibitory neurotransmitter in the brain. Note - Kaplitt is clearly the neurosurgical expert, and Matt During seems to be key to the use of a virus as a vector gene delivery system

When GABA is too weakly secreted, and hence in deficit, Parkinsons results, with its evident excessive uncontrolled neural activity of motor function. Proper levels of GABA appear to be useful if not critical to control the disease.

About Parkinson’s disease (conventional description)

Parkinson’s disease is a debilitating neurological disorder; a person’s lifetime risk of getting it is 1 chance in 1,000. The risk of developing Parkinson’s disease increases as one gets older. The symptoms are a resting tremor, slowness of movement, muscular rigidity, and an unstable posture. Not all of these four symptoms need to be present for a diagnosis of Parkinson’s disease.

Medication can help relieve the symptoms of Parkinson’s disease, especially in the early stages. As the disease progresses, the symptoms are more difficult to control. Surgery is then an option for some Parkinson’s disease patients.

Parkinson’s disease is caused by the loss of brain cells that make dopamine. Dopamine is a neurotransmitter that is needed for normal movement. The majority of these cells need to be lost before Parkinson’s disease symptoms are seen.


Neurologix's technique directly causes more GABA to be synthesized where it is needed, thus helping to calm the STN subthalmic nucleus over-activity - which is a core characteristic of Parkinsons, if not possibly an alternative interpretation of the actual disease itself.

The only technical point I sense I do not comprehend is how injecting a genetically modified virus into the brain tissue where GABA is synthesized, might not cause GABA synthesis in other tissues more widely than intended?

Can Kaplitt's methods result in overproduction of GABA, or alternately, can the genetically engineered viral infection only result in turning back on GABA production where it might otherwise only occur in a healthy patient, so the effect might prove to be self regulating in desirable manners? It appears at first glance to not be a concern.

It might be that Kaplitt has found a partial DNA fragment that can only result in GABA production where it originally occurred, and nowhere else in the body. If so, this might overcome plausible stumbling blocks of other genetically engineered attempts at treating Parkinson's.

The details of why the research team thinks there is a good case for this to work well over long term for the patient, might be interesting to learn about.

[ed - June 25 2007 - Mike Kaplitt's dad Dr. Martin Kaplitt who is COB of Neurologix just called me, to help clarify my questions re why this works, and does not cause an overproduction of GABA. Two main salient points - 1 - The blood brain barrier prevents the gene carrier of modified AAV Virus to not pass beyond the brain cavity, with the surgical procedure used to introduce the virus into the brain, and notably in proximity to the desired brain tissue desired to infect with the modified gene. 2 - GABA competes with some other factor (which Martin mentioned but I do not remember the specific name to) such that there is a constant regulation of free GABA versus the competing effect, with the result this works.

Martin also remarked that Dopamine based strategies for treating Parkinsons have their limits(described in the Neurologix patents) and this GABA restoration used by Neurologix is fundamentally a new strategy to treat Parkinson's not merely noted by the use of Gene Therapy, nor merely by the less common use of modified AAV vector as the means to infect the desired Gene per se, but notable in that the therapy targets an entirely new pathway to treat Parkinsons via the GABA route. ]

The experiment results were in a small phase 1 FDA test, where it is important to note that FDA Phase 1 clinical testing is mostly intended to address potential toxicity or dangers of a new pharma compound treatment, and not specifically intended to address a new treatment's efficacy.

Nevertheless, when something is novel and effective, there often are often hints in preliminary FDA Phase 1 tests that indicate the potential promise of a new method or pharma compound.

My impression is this is possibly stunning.

As yet far too early to claim a cure, but if ever a Phase 1 hinted that Parkinsons might have met its match, this hints of possible substantive success. This is discussed in an article at MSNBC and here in some greater depth in a recent Weill Cornell Neurosurgery news release dated June 21st 2007.

Kaplitt appears to have the insight, experimental expertise (Genetic engineering and Neurology) and deep technical understanding needed to tame the monster that Parkinsons is. I wish him and the Neurologix team all the best of luck in developing the real innovations undertaken.

Dr. Kaplitt seems to be a researcher who both observes closely, and tests his novel ideas well. Moreover the man has got game - patent game, and given he got his MD in 1995, he is likely going to be a very prolific innovator over his career.

Here are most of Kaplitt's patents and patent applications at present

US20070059290 Transcriptional regulation of target genes
US20060228776 PINK-1 promoter
US20060210538 Use of apotosis inhibiting compounds in degenerative neurological disorders
US20060129126 Infusion device and method for infusing material into the brain of a patient
US20060099179 Glutamic acid decarboxylase (GAD) based delivery system
US20050025746 Glutamic acid decarboxylase (GAD) based delivery systems
US6780409 Glutamic acid decarboxylase (GAD) based delivery system
US20030152914 Method for generating replication defective viral vectors that are helper free
US20030087264 Transcriptional regulation of target genes
US6503888 AAV-mediated delivery of DNA to cells of the nervous system
US20020091094 Glutamic acid decarboxylase (GAD) based delivery system
US6180613 AAV-mediated delivery of DNA to cells of the nervous system
US6162796 Method for transferring genes to the heart using AAV vectors
US6106824 Expression of growth associated protein B-50/GAP-43 in vitro and in vivo
US6040172 Defective DNA viral vector comprising a neural tissue-specific promoter for in vivo expression of a gene

I will also point out that the scientific advisory board (SAB) at Neurologix is substantive. Kaplitt has put together a SAB intellectual team that is notable for the breadth of the participants talents, most if not all experience directly relevant to the firm's efforts.

The Neuroligix SAB is comprised of people who include
1 - a surgeon for Parkinson's disease, who also is a member of the scientific advisory board for the Michael J. Fox Foundation,
2 - a
molecular neuroscientist,
3 - a psychiatrist highly skilled in
4- a neurologist specializing in
molecular and cellular changes in neural networks, focused on Epilepsy,
5 -
a pioneer of gene therapy of neurological diseases and human brain microdialysis,
6 - a
Professor of Molecular and Cellular Neuroscience,
aside from
Kaplitt's obvious brilliance.

Here are the company bios followed by academic research summaries of the SAB members, including that of the founder Dr. Michael Kaplitt

Andres M. Lozano, M.D. Ph.D.

Dr. Lozano is the acknowledged world leader in surgery for Parkinson's disease and other movement disorders, and is also an expert in surgery for epilepsy. Dr. Lozano has published over 100 papers and has recently edited a major book on this subject. He also directs a laboratory engaged in pioneering research attempting to identify potential causes of Parkinson's Disease. He is currently Professor of Neurosurgery and holds the Ronald Tasker Chair in Stereotactic and Functional Neurosurgery at The University of Toronto. Dr. Lozano received his MD from the University of Ottawa and Ph.D. from McGill University. He completed a residency in Neurosurgery at the Montreal Neurological Institute prior to joining the staff at The University of Toronto. He has held numerous official positions in Neurology and Neurosurgery societies, and is currently the Secretary of both the American Society for Stereotactic and Functional Neurosurgery and the World Society for Stereotactic and Functional Neurosurgery. He also serves on the editorial board of several major journals, and is a member of the scientific advisory board for the Michael J. Fox Foundation.


Keywords: Parkinson's disease, neuroprotection, neurophysiology, dopamine, functional neurosurgery

Research Interests
Parkinson's Disease and Functional Neurosurgery
Our laboratory is interested in understanding the causes of Parkinson's disease and in developing novel treatments. Our experiments aim at uncovering the mechanisms through which dopamine neurons die and developing novel strategies to prevent their death using experiments on models of Parkinson's disease.

A second focus of our laboratory is functional neurosurgery. In these studies we aim to improve our understanding of how disruptions in neural activity in the brain of human patients lead to subthalamic nucleus and various areas of the cortex to obtain direct recordings to cellular activity in these nuclei. These approaches help understand the pathogenesis of these disorders and are leading the development of novel treatment strategies.

Pubmed Publications
Perform an automatic PubMed search of this researcher's publications.

Andrew Brooks, Ph.D.
Dr. Brooks is the Director of the Bionomics Research and Technology Center (BRTC) at the Environmental and Occupational Health Science Institute of the University of Medicine and Dentistry of New Jersey. He is also the Associate Director of Technology Development at Rutgers University's Cell and DNA Repository and an Associate Professor of Environmental Medicine and Genetics at UMDNJ. Dr. Brooks is a molecular neuroscientist whose research focuses on deciphering the molecular mechanisms that underlie memory and learning. These studies investigate gene-environment interactions in the context of aging, neurodegenerative disease and neurotoxicant exposure. His group is also involved in the development of novel informatics approaches to better understand complex genomics-based data sets for diagnostic development.

Dr. Brooks’ laboratory has three main areas of interest. First, his group works on deciphering the molecular mechanisms that underlie memory and learning. They utilize a variety of technologies for genetic modification as well as investigate gene–environment interactions in the context of aging, neurodegenerative disease and neurotoxicant exposure. Their research utilizes many high-throughput genomics based technologies to study these areas. Second, his group is involved in the development of novel informatics approaches to better understand complex genomics-based data sets. The team has recently developed a novel method for interpreting complex gene expression data sets as a function of biological relevance. This approach is being utilized both in the basic science and clinical arenas. Lastly, Dr. Brooks’ team is engaged in a number of technology development programs. Currently, they are developing new applications in the area of transcript profiling and protein profiling that can be applied to both standard and novel technology platforms. More recently Dr. Brooks has been appointed Director of the AMDeC Microarray Resource Center, which helps coordinate all micro array and genomics related activities for New York State. Dr. Brooks has been actively involved with ABRF for a number of years and currently chairs the Microarray Research Group.

Eric J. Nestler, M.D., Ph.D.
Dr. Nestler is the Lou and Ellen McGinley Distinguished Chair in Psychiatric Research and Professor and Chairman of the Department of Psychiatry at the University of Texas Southwestern Medical Center. From 1992 to 2000, he was Director of the Abraham Ribicoff Research Facilities and of the Division of Molecular Psychiatry at Yale University. Dr. Nestler's research focuses on ways in which the brain responds to repeated perturbations under normal and pathological conditions, with a primary focus on drug addiction and depression. He has authored or edited seven books, and published more than 300 articles and reviews and 267 abstracts relating to the field of neuropsychopharmacology.

Dr. Nestler's awards and honors include the Pfizer Scholars Award (1987), Sloan Research Fellowship (1987), McKnight Scholar Award (1989), Efron Award of the American College of Neuropsychopharmacology (1994) and Pasarow Foundation Award for Neuropsychiatric Research (1998).

ACADEMIC RESEARCH SUMMARY - My laboratory is interested in understanding the molecular and cellular basis of neural and behavioral plasticity. One major focus of our group is on drug addiction: to characterize molecular and cellular adaptations induced in the brain after chronic administration of opiates, cocaine or other drugs of abuse. An important feature of this work is to relate specific molecular and cellular adaptations to drug-induced alterations in neuronal function and complex behavior that define an addicted state. A second major focus is on the long-term effects of stress and antidepressants on the brain in animal models of depression. We utilize methods of viral-mediated gene transfer and genetic mutations in mice (in particular, inducible, cell type-specific mutations) to establish causal relationships among molecular, cellular, and behavioral levels of analysis.

Daniel H. Lowenstein, M.D., Ph.D.
Dr. Lowenstein is Professor and Vice Chairman in the Department of Neurology at the University of California, San Francisco (UCSF), Founder and Director of the UCSF Epilepsy Center, and Director of Physician-Scientist Training Programs for the UCSF School of Medicine. He was previously at Harvard Medical School as the Dean for Medical Education and Carl W. Walter Professor of Neurology. During 2004, Dr. Lowenstein served as the President of the American Epilepsy Society.

His interests include the molecular and cellular changes in neural networks following seizure activity and injury and the contribution of neurogenesis to seizure-induced network reorganization in the adult central nervous system. He has received several national awards for excellence in teaching and numerous academic honors and awards, including the American Epilepsy Society's 2001 Basic Research Award. Most recently, Dr. Lowenstein's research has centered on approaches designed to advance understanding of the complex genetics that are thought to underlie a substantial portion of idiopathic epilepsies. In collaboration with other epilepsy researchers, he is working on the design of a venture entitled "The Epilepsy Phenome/Genome Project," with the intention of collecting detailed phenotypic and genotypic information on more than 5,000 patients in order to identify genetic mutations and post-translational mechanisms contributing to epilepsy.

Matthew J. During, M.D., DSc.

Dr. During is an internationally recognized leader in the fields of gene therapy of neurological diseases and human brain microdialysis, areas in which he is a world pioneer. He is currently Professor of Molecular Medicine and Pathology at University of Auckland in New Zealand and Director of the Molecular and Translational Neuroscience Laboratory, Department of Neurological Surgery, Weill Medical College of Cornell University. He also served as Director of the CNS Gene Therapy Center and Professor of Neurosurgery at Jefferson Medical College from 1998 through 2002.

At the University of Auckland, Dr. During directs major neuroscience and gene therapy programs. One of his most recent and important accomplishments in gene therapy field was completion of the first non-cancer CNS gene therapy trial, a subject of major articles in publications such as Science. In addition, Dr. During made a significant breakthrough in the development of a novel vaccine for stroke and epilepsy (again published in Science) as well as a novel oral gene delivery method for diseases like diabetes.

In addition to research and teaching, Dr. During has authored more than 100 groundbreaking papers in the fields of neuroscience, molecular biology, gene transfer and therapy, including many articles in such prestigious journals as Nature, Science, Nature Genetics and Nature Medicine.

Dr. During is a graduate of University of Auckland School of Medicine, and did further postgraduate training at M.I.T. (1985 - 1987), Harvard Medical School (1986 - 1989) and at Yale (1988 - 1989). He was on the Faculty at Yale University from 1989 through 1998, where he directed a program on the molecular basis of learning and memory, and headed Yale's first gene therapy protocol.

ACADEMIC RESEARCH SUMMARY - Research Areas - Our research interests are broad and range from the study of the molecular basis of learning and memory, to gene therapy of neurological disorders. The main common theme is the use of somatic cell gene transfer to study neuronal physiology and to treat human disease. Our research covers the full spectrum from molecular biology through to animal behaviour and human clinical trials. For our gene therapy program, in the first instance "proof of principle" experiments are conducted to test therapeutic concepts in an attempt to obtain phenotypic correction in models of neurological disease. Promising approaches are advanced to human clinical trials. Many of our research projects involve collaborations and our laboratory is of international standing and forms a key role in a major network of mammalian brain gene interventionists. Our gene therapy group is an international collaborative group of investigators at Auckland and Philadelphia.

Vectorology program
Our vectorology program is primarily orientated around adeno-associated virus (AAV) as a vector gene delivery system. Our efforts are focused on improvements in these systems including increased efficiency of gene transfer/transduction; stable and regulated transgene expression; gene silencing; vector targeting; and decreased toxicity/pathogenicity of the vector systems as well as development of animal models of neurological disease, including Parkinson's, Huntington's and Alzheimer's Disease.

Parkinson's Disease
We have an extensive Parkinson's Disease research program, ranging from generating novel genetic models of Parkinson's Disease, investigation of mechanisms underlying Parkinson's neuropathology, as well as the development of therapeutic strategies. Early work focused on dopamine replacement and growth factor strategies. More recently, we have developed a strategy to reset brain circuitry altered in Parkinson's. Following promising preclinical studies, we have obtained FDA approval for the world's first human Phase I clinical trial using a gene therapy approach for Parkinson's Disease.

Alzheimer's Disease/Huntington's Disease
New research directions for our lab include developing genetic models of Huntington's and Alzheimer's Diseases and the development of therapeutic strategies for these diseases.

Learning and Memory
We have a long-standing interest in the molecular mechanisms of learning and memory. Our current approach is focused on altering candidate molecular gene expression (signal transduction enzymes and transcription factors) in specific brain regions using viral vectors and defining alterations in brain neurochemistry and physiology which mediate phenotypic effects on learning and memory.

Our laboratory has a long-standing interest in the use of microdialysis in the conscious human brain. Our major efforts have been to determine the mechanisms underlying epilepsy specifically focusing on the GABergic and glutamatergic transmitter systems. In addition we have looked at effects of novel antiepileptic drugs (AEDs) on brain chemistry to define mechanisms of action as well as the use of AEDs as probes to look at receptor and transporter changes in the human epileptic brain. We are currently developing approaches for gene therapy of the epilepsies.

Vaccines for neurological disease
We are characterising genetic and protein vaccine approaches as potential prophylactic approaches for stroke and epilepsy.

Effects of Environment on Brain Structure and Function
We have an interest in the effects of environment on brain structure and function. We and others have found that complex social and physical stimulation increases new cell birth within the hippocampus. This process called neurogenesis has implications for learning and memory as well as neurological disease.

Michael G. Kaplitt, M.D. Ph.D.
Dr. Michael Kaplitt is an expert and innovator in gene therapy who was among the first scientists to publish on the use of viruses for direct gene delivery in the living brain. Dr. Kaplitt published a breakthrough study on the use of defective herpes simplex virus vectors in the brain, and along with Dr. During, he was the lead author on the first publication reporting on the use of adeno-associated virus (AAV) vectors in the brain.

Dr. Kaplitt is currently Assistant Professor of Neurosurgery, Director of Stereotactic and Functional Neurosurgery and Director of the Laboratory of Molecular Neurosurgery at Weill Medical College of Cornell University. He is also Clinical Assistant Attending, Division of Neurosurgery, Dept. of Surgery at Memorial-Sloan Kettering Cancer Center, and Adjunct Faculty, Laboratory of Neurobiology and Behavior at The Rockefeller University. In addition to his neurosurgical practice and laboratory research, Dr. Kaplitt has received several awards for his work and has authored more than 40 papers and book chapters on gene therapy and stereotactic and functional neurosurgery, including articles which have appeared in scientific magazines such as Nature Genetics and Proceedings of the National Academy of Sciences.

Following his neurosurgical residency, Dr. Kaplitt completed a fellowship in Stereotactic and Functional Neurosurgery with Dr. Andres Lozano at the University of Toronto, where he received sub-specialty training in surgery for Parkinson's Disease, other movement disorders, pain and epilepsy. Dr. Kaplitt, together with Dr. Arthur Loewy, edited an internationally recognized book on the subject of gene therapy in the brain, titled "Viral Vectors" and published by Academic Press. Due to the success of the first volume, Dr. Kaplitt and Dr. During are currently working on a revised volume at the request of the publisher. Dr. Kaplitt graduated magna cum laude in molecular biology from Princeton University.

Dr. Kaplitt received his MD degree from Cornell University School of Medicine in 1995, where he completed his residency in Neurosurgery. Dr. Kaplitt also received a Ph.D. degree in molecular neurobiology from Rockefeller University, where he performed his groundbreaking work in viral gene transfer to the brain.

Paul Greengard, Ph.D. Chairman

Dr. Paul Greengard is the Vincent Astor Professor of Molecular and Cellular Neuroscience at The Rockefeller University. He began his exploration of nerve cells in 1948 when he joined the Johns Hopkins biophysics laboratory then headed by Detlev Bronk. After receiving his Ph.D. from Johns Hopkins in 1953, Greengard spent five years in England receiving advanced training in brain biochemistry at the University of London, at Cambridge University, and at the National Institute of Medical Research.

Upon his return to the United States, Greengard worked as Director of the Department of Biochemistry at Geigy Research Laboratories, in Ardsley, New York for eight years. He has remained intensely interested in the applications of basic scientific knowledge to the development of therapeutic agents for treatment of various neurological and psychiatric diseases. In 1967, he left the pharmaceutical industry to return to academia. He spent one year as Visiting Professor at Albert Einstein College of Medicine and Vanderbilt University School of Medicine. From 1968 to 1983 Greengard served as Professor of Pharmacology and Psychiatry at Yale University, at which time he moved to his current position at The Rockefeller University.

Over the years, Greengard’s achievements have earned him many distinguished awards including the Metropolitan Life Foundation Award for Medical Research, The Charles A. Dana Award for Pioneering Achievements in Health, the Ralph W. Gerard Prize in Neuroscience from the Society for Neuroscience, The National Academy of Sciences Award in the Neurosciences, the Bristol-Myers Award for Distinguished Achievement in Neuroscience Research, the 3M Life Sciences Award of the Federation of American Societies for Experimental Biology. In the year 2000, Greengard was awarded the Nobel Prize in Physiology or Medicine.


The goals of our research group are to understand more fully the molecular basis of communication between neurons in the adult mammalian brain and to elucidate the molecular defects responsible for various neurological and psychiatric disorders.

Elucidation of the mechanism of action of neurotransmitters, therapeutic agents and drugs of abuse. Work over the past three decades has demonstrated that nerve cells communicate with each other through two mechanisms, referred to as fast and slow synaptic transmission. Fast-acting neurotransmitters, e.g., glutamate (excitatory) and GABA (inhibitory), achieve effects on their target cells within one millisecond, by virtue of opening ligand-operated ion channels. In contrast, all of the effects of the biogenic amine and peptide neurotransmitters, as well as many of the effects of glutamate and GABA, are achieved over hundreds of milliseconds to minutes, by slow synaptic transmission. This latter process is mediated through an enormously more complicated sequence of biochemical steps, involving second messengers, protein kinases, and protein phosphatases. Slow-acting neurotransmitters control the efficacy of fast synaptic transmission by regulating the state of phosphorylation of receptors for fast-acting neurotransmitters and thereby controlling the efficiency of the response of these postsynaptic receptors to the neurotransmitter. A major goal of our research at the present time is to elucidate the molecular mechanisms by which this regulation occurs. Our research uses techniques from the fields of molecular biology, cellular biology, biochemistry, electrophysiology and neuro-anatomy in a multidisciplinary approach to the problems of neuronal function and signal integration.

One major focus of our work is to elucidate the molecular and cellular basis of neuronal function and interactions in the basal ganglia. The basal ganglia play a critical role in the integration of sensorimotor, associative and limbic information to produce motor behaviors. In addition, abnormalities in dopaminergic, glutamatergic and serotonergic signaling in the basal ganglia have been implicated in many neurological and psychiatric disorders, including schizophrenia, Parkinson's disease, Huntington's disease, depression, anxiety, Attention Deficit Hyperactivity Disorder and drug abuse. The basal ganglia are composed of several subcortical nuclei, including the striatum, the globus pallidus, the subthalamic nucleus and the substantia nigra. The striatum is a central component of the basal ganglia as it integrates excitatory glutamatergic inputs, predominantly from the cortex and thalamus, with dopaminergic and serotonergic inputs from mesencephalon, and sends projections to the output structures of the basal ganglia.

Neurobiology of signaling in the brain. Our research group is elucidating the signal transduction pathways through which dopamine and other neurotransmitters elicit their physiological effects on their target neurons in the basal ganglia. We have found that about a dozen neurotransmitters which regulate the activity of these neurons do so in large measure by regulating the state of phosphorylation of a pivotal signaling switch referred to by the acronym DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein, Mr32kDA). They do so through a variety of mechanisms involving increased or decreased phosphorylation or increased or decreased dephosphorylation. We have found four specific residues in DARPP-32 that are phosphorylated by distinct protein kinases and dephosphorylated by distinct protein phosphatases. The DARPP-32 molecule itself can act either as an inhibitor of cyclic AMP-dependent protein kinase or as an inhibitor of protein phosphatase-1, depending upon the particular residue that is phosphorylated. This is the first known example of a molecule that can act either as a protein kinase or phosphatase inhibitor. The state of phosphorylation of DARPP-32, through control of protein kinase and phosphatase activities, regulates the state of phosphorylation and activity of virtually every known physiological effector, including a variety of ion pumps, ion channels, neurotransmitter receptors and transcription factors. Dopaminoceptive neurons integrate all information coming into the neostriatum and are the only efferent pathway out of the striatum. DARPP-32 provides a molecular mechanism by which all efferent information is integrated and converted into a meaningful physiological response. Animals with targeted deletion of the DARPP-32 gene show a total loss of effectiveness of dopamine, antipsychotic drugs and substances of abuse, including cocaine, amphetamine, LSD, PCP (angel dust), opiates, marijuana, alcohol, nicotine and caffeine. This research program has clarified a great deal of the signaling machinery involved in dopamine action and the action of other neurotransmitters that interact with the dopamine pathway, has elucidated new principles of signal transduction and is of clinical relevance, providing a variety of new targets for the development of drugs for the treatment of several major psychiatric and neurological disorders.

Finally, we have found recently that DARPP-32 plays a major role in signaling between nerve cells in many regions of the brain in addition to the dopamine-innervated regions. For example, the widely used antidepressant drug Prozac regulates DARPP-32 phosphorylation in the cortex and hippocampus. Moreover, the antidepressant effects of Prozac observed in wild-type mice are abolished in mice lacking the DARPP-32 gene. These data indicate that the essential role of DARPP-32 in cell signaling in the brain extends far beyond the dopamine cell-signaling system and appears to involve a large number of neurotransmitters in many brain regions.

Alzheimer Amyloid Precursor Protein (APP). We have demonstrated that the relative amounts of APP that are converted to the nontoxic soluble form of APP (APPs) and the toxic beta-amyloid are controlled by protein phosphorylation and dephosphorylation mechanisms. Thus, activators of various protein kinases, as well as inhibitors of various protein phosphatases, reduce the amount of beta-amyloid formed by nerve cells. We are now determining the components of the signal transduction cascade that are responsible for the regulation of APP breakdown, and the formation of beta-amyloid, with the aim of developing new targets for the treatment of Alzheimer's disease.


Here is the firm's press release describing the early Phase 1 results.

Neurologix Announces Publication of Landmark Gene Therapy Study Demonstrating Safety and Statistically Significant Improvement in Patients With Advanced Parkinson's Disease

FORT LEE, N.J.--(BUSINESS WIRE)--June 21, 2007--Neurologix, Inc. (OTCBB:NRGX) today announced the publication in the June 23 issue of the journal The Lancet of positive results from the first ever gene therapy trial for Parkinson's disease and the first report of direct gene transfer into a patient's own brain cells for any adult neurodegenerative disease.

The open label Phase 1 study, conducted in 12 patients with advanced Parkinson's disease demonstrated both a lack of adverse events related to the gene therapy procedure and statistically significant improvements from baseline in both clinical symptoms and abnormal brain metabolism (as measured by positron emission tomography, or PET scanning). Although all patients had symptoms on both sides of the body, the procedure was performed on only one side of the brain, enabling the untreated side to serve as a study control. The reported improvements were observed primarily on the treated side of the body beginning three months after the gene therapy procedure and persisted through the 12 months formal study period.

Neurologix sponsored the study as part of its ongoing efforts to develop this and other gene therapy approaches to the treatment of neurodegenerative and metabolic diseases. Principal investigators Michael G. Kaplitt, MD, PhD, and Matthew J. During, MD, PhD, performed the procedures at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. Andrew Feigin, MD and David Eidelberg, MD of the Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System performed the clinical evaluations and the PET scans. Neurologix scientists were also co-investigators in the study.

"This ground-breaking study represents not only an encouraging first step in the development of a promising new approach to Parkinson's disease therapy, but also provides a platform to translate a variety of new gene therapy agents into human clinical trials for many devastating brain disorders," said Paul Greengard, PhD, chairman of the Neurologix Scientific Advisory Board and recipient of the 2000 Nobel Prize for Physiology or Medicine for his work related to how brain cells communicate. "The significant and sustained improvements in clinical symptoms following treatment of only one side of the brain are impressive. Moreover, the PET results offer an important window into the function of the living brain in these patients, which supports a normalization of brain activity specific to the treated hemisphere."

The study used an adeno-associated virus (AAV) vector to deliver an inhibitory gene (glutamic acid decarboxylase or "GAD") to the subthalmic nucleus (STN) of the brain. In Parkinson's disease, STN activity is abnormally increased, largely due to a deficit in GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter in the brain. Increasing GAD causes more GABA to be synthesized, thus helping to calm the STN over-activity. The value of this strategy has been demonstrated in previous human studies where reducing STN activity by either electrical stimulation or lesioning can help ameliorate the symptoms of advanced Parkinson's disease.

The Phase 1 study was not specifically designed to assess efficacy. Nonetheless, the researchers reported the clinical outcomes to be very encouraging, with treated patients showing significant improvement in both the "on" and "off" states of their illness (the time periods in which they achieve or do not realize benefit from drug therapy) beginning at three months following surgery and continuing through the end of the study. These improvements occurred predominantly on the side of the body corresponding to the side of the brain receiving treatment. Moreover, the absence of change at the earliest time point following treatment suggests that the improvement was not likely due to the surgical lesioning of the targeted brain region, as surgical approaches typically give rise to immediate, short-lasting benefit around the time of surgery, while prior studies of AAV-mediated gene therapy show that gene expression gradually increases to a maximal level over a period of weeks.

"We are very encouraged by the results of this trial and its publication in such a prestigious journal," said John Mordock, Neurologix President and Chief Executive Officer. "Since the inception of the company, we have been a leader in developing gene therapy for neurological disease, and we feel that rigorous peer-review and publication of the results from this first-ever trial is an important milestone for this entire field. These promising observations certainly warrant further, more definitive testing of Neurologix's technology, and we anticipate beginning a larger Phase 2 study in Parkinson's disease later this year. Moreover, the results also provide a solid foundation for the development of our other therapeutic programs, including epilepsy where we plan to initiate a Phase 1 gene therapy study this year."

Study Design

The study included 12 patients with advanced Parkinson's disease, 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. 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 less than 0.005). Nine of the 12 patients showed an average of 37% and five of these patients had substantial improvement of between 40% and 65%. Clinical improvement also correlated well to metabolic changes in glucose utilization as measured by PET scan. The PET scan data revealed a significant improvement (p less than 0.001) in brain metabolism on the treated side of the brain compared to the untreated side. No adverse events related to the gene therapy procedure were reported throughout the duration of the 12-month study, or in the subsequent two years since the study formally ended.

About Neurologix

Neurologix, Inc. is a development-stage company engaged in the research and development of proprietary treatments for disorders of the brain and central nervous system utilizing gene therapies. The Company's initial development efforts are focused on gene therapy for treating Parkinson's disease, epilepsy and other neurodegenerative and metabolic disorders. Neurologix's core technology, "NLX," is currently in the clinical development stages, having recently been tested in a company-sponsored Phase I human clinical trial to treat Parkinson's disease.

Cautionary Statement Regarding Forward-looking Statements

This news release includes certain statements of the Company that may constitute "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and which are made pursuant to the Private Securities Litigation Reform Act of 1995. These forward-looking statements and other information relating to the Company are based upon the beliefs of management and assumptions made by and information currently available to the Company. Forward-looking statements include statements concerning plans, objectives, goals, strategies, future events, or performance, as well as underlying assumptions and statements that are other than statements of historical fact. When used in this document, the words "expects," "promises," "anticipates," "estimates," "plans," "intends," "projects," "predicts," "believes," "may" or "should," and similar expressions, are intended to identify forward-looking statements. These statements reflect the current view of the Company's management with respect to future events. Many factors could cause the actual results, performance or achievements of the Company to be materially different from any future results, performance or achievements that may be expressed or implied by such forward-looking statements, including, but not limited to, the following:

The Company is still in the development stage and has not generated any revenues. From inception through March 31, 2007, it incurred net losses and negative cash flows from operating activities of approximately $22.7 million and $17.4 million, respectively. Management believes that the Company will continue to incur net losses and cash flow deficiencies from operating activities for the foreseeable future. Because it may take years to develop, test and obtain regulatory approval for a gene-based therapy product before it can be sold, the Company likely will continue to incur significant losses for the foreseeable future. Accordingly, it may never be profitable and, if it does become profitable, it may be unable to sustain profitability.

In order to obtain the regulatory approvals necessary to commercialize its current or future product candidates, from time to time the Company will need to raise funds through public or private equity offerings, debt financings or additional corporate collaboration and licensing arrangements. Availability of financing depends upon a number of factors beyond the Company's control, including market conditions and interest rates. The Company does not know whether additional financing will be available when needed, or if available, will be on acceptable or favorable terms to it or its stockholders. Management believes that the Company's current resources will enable it to continue as a going concern through at least March 31, 2008.

The Company will need to conduct future clinical trials for treatment of Parkinson's disease using the Company's NLX technology. If the trials prove unsuccessful, future operations and the potential for profitability will be materially adversely affected and the business may not succeed.

There is no assurance as to when, or if, the Company will be able to successfully receive permission from the FDA to begin a Phase I safety trial for treatment of epilepsy.

Other factors and assumptions not identified above could also cause the actual results to differ materially from those set forth in the forward-looking statements. Additional information regarding factors that could cause results to differ materially from management's expectations is found in the section entitled "Risk Factors" in the Company's 2006 Annual Report on Form 10-KSB. Although the Company believes these assumptions are reasonable, no assurance can be given that they will prove correct. Accordingly, you should not rely upon forward-looking statements as a prediction of actual results. Further, the Company undertakes no obligation to update forward-looking statements after the date they are made or to conform the statements to actual results or changes in the Company's expectations.

Neurologix, Inc.
Marc Panoff, CFO, 201-592-6451 (Investors)
Kureczka/Martin Associates
Joan Kureczka, 415-821-2413 (Media)

SOURCE: Neurologix, Inc.


here are some more links to info about Dr. Michael Kaplitt

Crains New Yorkers Top 40 under 40
Weill Cornell Physicians listing

New York Best Doctors June 2004
Popular Science - Gambling on Gene Therapy
( ED - and winning is my guess)
Princeton Alumni Weekly October 22, 2003: A moment with...Michael Kaplitt ’87

Weill-CU/Auckland study shows efficacy of gene therapy for Parkinson's


Also I wish to highlight the apparent correlation of exposure to the metallic element / mineral Manganese, as a seemingly more than just a curious potential cause of Parkinsons, or at least Parkinsons like symptoms.

This is explored here in a web article from UC Davis and here at the University of Washington where there is apparently some parkinsons related data in dietary minerals of both manganese and iron .

This is a clear case where in the extreme taking too much of the wrong over the counter minerals (in for example vitamin supplements) one needs to exert caution, especially if already suffering from Parkinsons. Yet apparently some Manganese is required for healthy body functions? Are dietary supplements of Manganese ever properly indicated or justified? I do not know.

One osteopath physician describes some of these issues from a more experienced perspective than ever I could - Dr. Joseph Mercola

And here is an abstract of an academic research article substantiating the neurotoxic effects of manganese exposure to the nigrostriatal dopaminergic system, resulting in Parkinsons like effects. The main subject of the article seems actually to be effects of a particular protein kinase in the phenomena of damage to dopaminergic cells by manganese. I have not had time to look at the actual article, but hints are there in the abstract as to implied cautions re Manganese exposure.

Aside from obscure industrial sources of manganese exposure, one might be interested to know that stainless steel and aluminum foil both seem to have varying amounts of manganese in the practical alloys. The extent naturally will vary, but this might not be as well controlled in food cookware and aluminum foil as one might desire in the context of manganese risks in Parkinsons like issues.

A quick search indicates that typical aluminum foils might contain up to 1% manganese, typically fractional %. Most stainless steels have comparable low concentration, but there is one stainless variant that is called manganese substituted stainless steel that is curious in having 4% manganese... If this happened to be "accidentally" used in some stainless cookware and used to cook acidic foods regularly, my guess is this might be a curious area to investigate for a correlation to Parkinson's like symptoms in folks not exposed to industrial sources.

And excerpt from here
describes the stainless steel variant.

Manganese Substituted Stainless Steels (2XX or S2XXXX)

The AISI 200 series of stainless steels (S2XXXX) was developed during the 1930’s. These alloys were used during the Korean War to preserve nickel. About 4 wt% of the nickel is replaced by manganese with small (<0.25>

A number of stainless steel alloys in this classification have the trade name "Nitronic". These alloys tend to have higher strength and good wear resistance. Some examples are Nitronic 50 (21.2 wt% chromium, 12.5 wt% nickel, 2.5 wt% molybdenum, and 5 wt% manganese) with corrosion resistance better than AISI 316 and Nitronic 60 (17.0 wt% chromium, 8.5 wt% nickel, 4 wt% silicon, and 8 wt% chromium) with excellent wear resistance.


Just playing the amateur chemist for a nanosecond, would hint to me that some types of foods - likely more acidic in nature, would be more probable to leach some hypothetical small amounts of manganese, than foods closer to pH neutral? Which I do not know, but this as high alkalinity cooking with the wrong cookware that bore Manganese might be not so desirable ? It would be curious to test, as some stainless steels and aluminum foil might become an inadvertent health hazard in the wrong circumstances. Just speculation, but not entirely without rationale.

Far more notable is that welders can often be exposed to more directly hazardous Manganese fumes from some welding metallurgies, as will folks who do work in some basic metals / metallurgy processes where manganese fumes or vapors might be created at high temperatures. As usual, read your MSDS's and act accordingly.

Here is a link to a properly described MSDS for manganese oxide at the well respected chemical firm JT Baker, which correctly indicates the potential for central nervous system disorders and Parkinson's like symptoms. Some manganese element and inorganic manganese compound MSDS's are not so complete, nor as thorough. My compliments to JT Baker for doing it right. JT Baker makes well engineered products, I might add.

AUG 8th 2007.
I found an especially compelling web discussion about the correlation between the use of Manganese Dioxide ceramics glazes in RAKU Pottery firing and parkinsons symptoms here .

The discussion is almost shocking, as I used to do some pottery wheel work long long ago, although I did little glaze firing, I did paint glazes onto my works. This is indeed a warning regarding glazes other than those which are lead based. Given the possibility that manganese dioxide ceramics glazes might be prevalent in artwork and home made ceramics (cookware?) this is a warning light that is BRIGHT RED as in Beware. Given that some artlike glazes
(yielding hues ranging from brown to pink and purple) might have very high concentrations of Manganese Dioxides, this is likely a stronger acting effect than the stainless steel curiousity I describe above.

A further but Very Important Note - Please visit the Michael J Fox Foundation for lots of good useful information about Parkinsons disease, research, and treatments existing and being developed. Superbly focused, practically oriented research efforts, bearing down like a laser to attempt to cure this terrible disease.

Michael deserves profuse compliments for the superb work he is doing through his foundation, as do the foundation team members. The team and its efforts are substantive and highly focused on practical innovations that can have large impacts on clinical results.

FOCUSED on important matters of where to best use all the intellectual horsepower - for the greater good ! Often implied in many research efforts, but often not done well .... but Mike's Got It Right Here !!!

My sincerest respect goes out to Michael, as well as best wishes to him for a speedy recovery from his illness.

God Bless You Mike !

You are a hell of a great role model to emulate !!
p.s. I wrote this article after reading an earlier news item at MSNBC and observing what was a very unusual advance in the quest to improve Parkinsons treatment prognoses. So MSNBC, as others had it first(it was released on news wires), but I might have written this fairly well, as Dr. Martin Kaplitt COB indicated as he complimented me on this article.

My compliments go back to the excellent team at Neurologix for superb thoughtful, applied medical research and development. All the respect goes out to this superb team !

NOTE - for some more interesting articles on another novel biotech firm - this one innovating in cancer pharmaceuticals, see the following prior posts of mine on Adherex Technology, a firm using Cadherin Cell Adhesion chemistry, to selectively and safely kill a good portion of tumor tissue, among other pharma strategies.







Post a Comment

Links to this post:

Create a Link

<< Home

Enter your email address:

Delivered by FeedBurner

Subscribe to Wendmans Views on Nanotech by Email