PND  Research   
NIH (National Institutes of Health) SSADH Study Authorized
Note from Dr. Phil Pearl  5/13/2012

We have at long last received approval from the NIH to begin studies of SSADH deficiency patients on taurine. This is a prelude to a study we anticipate in the not too, too distant future of SGS using the same biomarkers, now that the rights have been acquired by the NIH from the pharmaceutical company and we are working on approval to begin this experimental agent. We need to show we can meet recruitment goals with this first phase.

Please send an update with your child’s current age, weight, and whether he or she is taking taurine. If so, what brand (hopefully GNC, to keep this uniform) and what dose? Only patients age 12 and over can participate at this time, and this is currently limited to US citizens.

We will want to be sure your ABAS form is updated and we will then schedule you to be seen at the NIH to embark on a series of test procedures.

The protocol involves baseline testing and repeat following three months of taurine therapy at the target dose. The tests are:

·         Flumazenil-ligand brain PET (for patients > 18 years only)

·         Transcranial magnetic stimulation

·         MR spectroscopy for quantitation of GABA and related metabolites

·         CSF for quantitation of GABA and related metabolites

·         Neuropsychological evaluation

·         EEG

The tests will be done also at a 3 month interval “off” taurine, so it is fine to enter whether your child is currently on or off the taurine.

If you are interested in being involved in this study please email myself at ppearl@childrensnational.org and Danniele Provost at Provost@cnmc.org. 

Thank you.

Phillip L. Pearl, M.D.
Division Chief, Child Neurology
Children's National Medical Center
Professor of Pediatrics, Neurology, and Music
The George Washington University School of Medicine and Columbian College of Arts and Sciences
Washington, D.C.
Phone 202-476-2120
Fax 202-476-5226
E-mail ppearl@childrensnational.org
 

National Institute of Health (NIH) Clinical Research Study
Protocol Number: 05-N-0224
Cortical Excitability in Succinic Semialdehyde Dehydrogenase Deficiency Patients

Summary
This study will measure brain excitability in patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, and in their parents.  SSADH is a rare inherited disease in which changes in certain brain chemicals affect brain cell activity.  Symptoms vary greatly among patients, and may include mental retardation, impaired ability to coordinate movements, and delay in language and speech development.  Other symptoms may include poor muscle tone, uncontrolled seizures and other neurological or behavioral abnormalities.  Test findings in patients and their parents will be compared with those of healthy normal volunteers.

The participants undergo the following:

Transcranial Magnetic Simulation (TMS)
Magnetic Resonance Imaging (MRI)
Electroencephalography (EEG)
Sleep study and Multiple Sleep Latency onset Testing (MSLT)
Nerve conduction studies


National Institute of Health (NIH) Clinical Research Study
Protocol Number: 05-N-0022
PET Imaging of GABA Receptors in Succinic Semialdehyde Dehydrogenase Deficiency

Summary:
This study will use brain imaging to map brain cell receptors for a chemical called GABA, a chemical that inhibits the activities of nerve cells.  The study includes patients with succinic semialdehyde dehydrogenase deficiency, or SSADH (a disorder in which an enzyme deficiency disrupts GABA metabolism), their parents, and healthy volunteers.  SSADH deficiency causes various neurological and neuromuscular problems, including mild to severe mental retardation, delays in acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), delay in language and speech development, and other symptoms.

Patients undergo magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning.

                          

SSADH Clinical Study Update

The study represents clinical protocols to assess the distribution and amount of GABA receptors, as well as neurophysiologic measures of cortical excitation versus inhibition in patients with SSADH deficiency. The study hypothesizes that chronic exposure to elevated GABA levels in the brain leads to down regulation of GABA receptors and subsequent reduction of GABA-mediated neuroinhibition.  The major objectives of this study are:1) to measure binding and distribution of brain GABA receptor utilizing 11C-flumazenil PET scans in patients with SSADH deficiency compared with controls and obligate heterozygote carriers; and 2) to obtain measurable neurophysiologic parameters of cortical excitability and inhibition utilizing TMS in patients with SSADH deficiency compared with controls and obligate heterozygote carriers.

A database of approximately 100 patients with SSADH has been identified through the clinical population seen at Children's National Medical Center and the published literature. In addition, there is an ongoing study utilizing a questionnaire for systematic data collections and analysis. This has enabled entry of more comprehensive and reliable data on 57 patients enrolled to date. This work represents the first set of clinical studies of patients with SSADH beyond the collection of clinical and laboratory data to begin to characterize this disorder and its natural history. The information gathered from this study will also be utilized to develop biomarkers for clinical trials. SSADH Study. For more information or if you are interested in participating in the study please email them at michael.gibson@chp.com or ppearl@cnmc.org

Knockout SSADH Mouse Model

The use of transgenic mice has begun to revolutionize the study of human inborn errors of metabolism. Disruption of specific genes in mice enables a researcher to study the "human" counterpart disease in a model system (mouse) which produces rapidly. This approach has recently been applied to SSADH deficiency. In November of 1999, the first mice with genetically altered SSADH were born. These animals have a short life span, and manifest behavioral and gait abnormalities as seen in the human disease. In addition, seizures are a common finding, and may ultimately be the cause of death. These new knockout mice are the subject of intense investigation, and new therapeutic approaches are being attempted in them. The development of useful therapeutics will ultimately have important benefits to those with the human disease. This work is under the supervision of Dr. K. Michael Gibson, Associate Professor, Department of Molecular and Medical Genetics, Oregon Health Sciences University.Recently, Dr. Gibson was awarded a research grant through NIH to help support this important work.

Avigen's AV201 (an AAV Vector containing the AADC gene)

Avigen's AV201 (an AAV Vector containing the AADC gene)For an update on the Avigen clinical trial of AV201 for Parkinson's disease, please visit the Avigen web site from the link below.  Information regarding AV201 is listed under "Investors" then select "Press Releases".
www.avigen.com

Avigen Announces Encouraging Early Data from Parkinson's Disease Clinical Trial Evidence for First Successful Gene Transfer of AADC Gene in Humans

( taken from Avigen website Press Releases www.avigen.com)

Alameda, CA, July 18, 2005 - Avigen, Inc. (Nasdaq: AVGN), today announced encouraging results from the first patient treated in a Phase I/II clinical trial of AV201, the Company's drug candidate for the treatment of mid- to later-stage Parkinson's disease.   The results from positron emission tomography (PET) brain scans obtained six months after AV201 infusion indicated an increased activity of the gene product, aromatic L-amino acid decarboxylase (AADC) in the targeted area of the brain, compared with the patient's pre-treatment PET scans. These findings are consistent with increased dopamine production and transgene expression.

In Parkinson's disease, brain dopamine concentrations decline, causing the main symptoms of muscle rigidity, slow movements, difficulty walking, and poor balance.  Levodopa, the first-line drug for treating symptoms of the disease requires AADC in order to be converted to dopamine. However, over time AADC production in the brain also declines as Parkinson's disease progresses, making levodopa less effective.  The mid- to later-stages of Parkinson's disease are often complicated by the toxic side effects associated with the higher doses of levodopa required to manage the disease's signs and symptoms. AV201 is designed to restore the activity of AADC in the brain, thereby extending the therapeutic usefulness and life of levodopa while avoiding side effects.

The Phase I/II clinical trial of  AV201 in Parkinson's disease was initiated in December, 2004, at the University of California San Francisco (UCSF) and Lawrence Berkeley National Laboratory (LBNL). The study's Principal Investigator, Michael Aminoff, M.D., D.Sc., Director of the University of California-San Francisco Parkinson's Disease Clinic & Clinical Research Center, said, "This is an exciting beginning and a first for us: evidence of successful AADC gene transfer into humans. Most importantly for our patient, the procedure and gene appear to be safe. We're pleased with how well AV201 is being tolerated." Dr. Phillip Starr, neurosurgeon for the first patient in the study, added: "Based on the PET scans, it appears that the procedure and the use of convection-enhanced delivery to optimize the
spread of AV201 worked as well as we could have hoped. We are enthusiastic about enrolling additional patients."

In another first, by using the dopamine tracer [18F] fluorometatyrosine (FMT)-based PET scanning rather than conventional fluorodopa PET, clinicians were able to visualize evidence of AADC gene expression with greater specificity.  The use of FMT-PET technology was pioneered at LBNL by William Jagust, M.D., a neurologist and the Faculty Senior Scientist at LBNL and professor of Public Health and Neuroscience at UC Berkeley, and Jamie Eberling, staff scientist at LBNL and Associate Professor of Neurology at UC Davis. "The tracer is an excellent measure of gene expression," commented Eberling. "FMT-PET studies in animal models of Parkinson's disease have shown sustained AADC gene expression for more than 5 years after convection-enhanced gene delivery, along with sustained motor improvement," commented Dr. Jagust.  "In this study, we are evaluating FMT-PET in individuals with Parkinson's disease as a surrogate marker of AADC activity and gene transfer. We are visualizing evidence of successful AADC gene transfer in the human brain for the first time. Both the apparent level and the duration of AADC expression are greater than any of us had anticipated, given the low dose of AV201 with which we began the study."

"These results did exceed our expectations, and we are encouraged that we are on the right track," said Dr. Dawn McGuire, a neurologist and Avigen's Chief Medical Officer.  "It is, of course, too early to determine the therapeutic benefit or duration of gene expression. However, the value of this research cannot be underestimated, both for the individuals afflicted with Parkinson's disease and for understanding the potential of gene therapy in neurologic disease."
On April 5, 2005 Avigen announced that it will focus on the development of traditional pharmaceutical products, particularly small molecules and biologics. As part of the decision, the Company indicated it would divest its proprietary AAV technology but was committed to ensuring the continuation of the ongoing clinical programs, including the AV201 Program in Parkinson's disease.

Commenting on the impact of the trial and the strategic decision to reposition the Company, Kenneth G. Chahine, Ph.D., J.D., Avigen's President and CEO said, "We chose this approach to treating Parkinson's disease not only for its therapeutic potential, but also the potential of visualizing AV201 activity using PET imaging.  Therefore, we are very encouraged by these results which underscore the pioneering work of Avigen and its collaborators to provide novel therapeutics for neurological disorders."

Dr. Chahine continued, "This news reinforces the confidence we've always had in our AAV gene therapy program and its potential, but does not change our longer term strategic vision to seek external funding for the AAV technology. At this time, we are in advanced discussions with multiple parties who have the resources and commitment necessary to secure the long-term future and success of our AAV technology, including this very exciting Parkinson's trial. As we move through this process, foremost in our minds is to evaluate our options based on which one will deliver the best long-term value to our shareholders. "

About Parkinson's Disease and AV201
Parkinson's disease (PD) is the second most common degenerative neurological disease after Alzheimer's disease, and is characterized by tremor, stiffness of the limbs and trunk, slowness of movement (bradykinesia), and poor balance. PD results from the death of specialized dopamine-producing cells in the brain. More than 2 million individuals in the United States and Europe are afflicted with Parkinson's disease. The primary and most effective treatment for this debilitating movement disorder is oral administration of levodopa, which is converted in the brain by the enzyme AADC, or dopa decarboxylase, into dopamine. As Parkinson's disease progresses, however, levodopa typically becomes less effective, believed due at least in part to the decline in concentrations of AADC resulting from continued neurodegeneration and cell death. Using higher levodopa doses in an attempt to compensate for less efficient conversion to dopamine often leads to intolerable side effects or toxicity. Avigen's AV201 is designed to restore the therapeutic effectiveness of levodopa by infusing the gene for AADC into the brain of patients, thus improving dopamine production.  AV201 is an AAV vector containing the gene for human AADC which is delivered directly to the striatum, the part of the brain requiring dopamine to control movement. The patient and physician potentially can regulate the activity of AADC by raising or lowering the amount of levodopa taken. "This functional 'on-off' switch potentially enhances the safety of AV201 gene therapy," commented Dr. McGuire.

Early research conducted in animal models was performed by Krzysztof Bankiewicz, M.D., Ph.D., and Professor of Neurological Surgery at UCSF. Dr. Bankiewicz helped pioneer convection-enhanced delivery, and initiated its use to deliver AAV-AADC in animal models of Parkinson's disease. Studies have demonstrated AADC expression for more than 5 years after a single administration of AAV-AADC, along with continued therapeutic benefit in Parkinsonian nonhuman primates. These results encouraged Avigen to move "from bench to bedside" with the current Phase I-II clinical trial, designed to evaluate the safety of increasing doses of AV201 in individuals with mid-to-later-stage Parkinson's disease.

In December of 2005 Avigen handed over there AV201 clinical trial to Genzyme ( 2005 Press Releases  December 21, 2005 Avigen's Gene Therapy Technology Acquired by Genzyme  www.genzyme.com )