Neural Repair

The

os Angeles

Neurosurgical Institut

THE FOUNDATION FOR NEURAL REPAIR at the LANSI

Leading Edge Neuroscience Research at the Los Angeles Neurosurgical Institute

Integrating Research and Patient Care

The Foundation for Neural Repair at the Los Angeles Neurosurgical Institute is a California Not-
for-Profit Foundation (501c(3). In addition to providing comprehensive clinical services for the
full range of neurological conditions, the Foundation for Neural Repair at the LANSI conducts an
active, leading-edge neuroscience research program. In this program, specialists integrate both
basic and clinical aspects of scientific knowledge and technology to address the specific challenges
of intractable illness.

The Los Angeles Neurosurgical Institute conducts research in three main laboratories:

Human Neural Stem Cell Therapy Neurosurgical Laboratory
Basic Neurophysiology and Cognitive Neurosciences Laboratories
Brain Imaging Laboratory

Human Neural Stem Cell Therapy Neurosurgical Laboratory

1.Molecular mechanisms of epilepsy

The epilepsies are disorders of neuronal excitability. Formation of new contacts between neurons,
synaptic reorganization and changes in synaptic morphology are the structural correlates of
epileptic activities. Several genes and biochemical pathways have been demonstrated to be related
to the development of epilepsy. In several models of epilepsy it has been demonstrated that
expression of growth related genes such as c-fos, BDNF, NGF, GAP-43, and etc. is induced
during synaptic remodeling. Brain regions which are involved in the epileptic synaptic remodeling
such as hippocampus and several areas of the cerebral cortex express a set of regulatory genes that
are essential for the neuronal plasticity. Expression and functioning of regulatory molecules is
highly coordinated and regulated by both intrinsic and extrinsic factors. One of the major reasons
for developing epilepsy's is malfunctioning of these regulatory mechanisms. Both genetic changes
(mutations) and physically damaging conditions such as injury and stroke may cause changes in
the regulatory mechanisms and result in uncontrolled growth and synaptic remodeling.
Unfortunately, very little is known about changes of regulatory mechanisms in epileptic human
brain. We propose to analyze molecular mechanisms of epilepsy using surgically removed human
neuronal tissue. This research will involve analyses of epileptic neuronal tissue using several
different approaches:

1. Histochemical characterization of structural changes in the epileptic neuronal tissue. This will
involve identification of morphological changes in the epileptic brain using different
immunohistochemical and microscopic imaging techniques.

2. Neurophysiological characterization of functional changes in the epileptic neuronal tissue. We
will analyze changes in synaptic connectivity and responses to different stimuli.
Results from the structural and functional analyses will be used to classify different cases of
epilepsy and correlate these changes with changes in molecular regulatory mechanisms.

3. Characterization of the molecular regulatory mechanisms in the epileptic neuronal tissue.
Progress in genomic research has lead to the development of techniques which allow detection of
expression of hundreds and thousands of genes simultaneously. We will characterize the
expression of networks of regulatory molecules in the epileptic neuronal tissue in order to
understand possible changes in the regulatory mechanisms. Identification of changes in the
molecular regulatory mechanisms creates a basis for identification of possible targets for
development of clinical treatments of epilepsy patients.

4. Development of methods to culture neuronal tissue from the epileptic brain. Accomplishing
this objective will create unique opportunity to analyze neurons in controlled conditions and
compare "normal" and "epileptic" neurons. Both neurophysiological and molecular biology
methods will be used to characterize individual "epileptic" neurons in vitro.
Results of this proposed research will form a solid bases to develop new clinical treatments of
epilepsy based on the molecular changes that take place in the epileptic brain.

2. Spinal cord injury

Two serious problems have to be solved in order to achieve recovery of function after spinal cord
injury. The first problem is that neurons do not regenerate in the spinal cord and the second is that
there is no natural way to replace lost neurons in the spinal cord. We propose to address both of
these problems in order to stimulate functional recovery of injured spinal cords.
In the first project we will develop methods to stimulate regeneration of spinal cord neurons using
techniques of genetic engineering. We will change genetic program of spinal cord neurons in a way
that adult neurons become "younger", more similar to the developing neurons that are able to
regenerate. For these purposes we will stimulate "mastergenes" of neuronal differentiation which
will turn on a whole cascade of gene regulatory events and lead to the regeneration. Initially, we
will develop treatments using neuronal cells in culture and animal models. The next step will be to
apply these techniques to spinal cord patients. To speed up the human applications we will use
human neurons in many experiments.

In the second project we will develop methods to generate genetically engineered neuronal cells
for transplantation into the spinal cord in order to replace lost neurons and obtain meaningful
functional regeneration. Recently, it has been demonstrated that the entire ventricular neuraxis
including spinal cord of the adult mammalian nervous system contain multipotent stem cells .
These multipotent stem cells divide and expand in response to growth factors, and develop into
different neuronal cell types (neurons, astrocytes and oligodendrocytes). Progress in the stem cell
transplantation experiments using experimental animals suggests that these cells can be
successfully used as a neuronal replacement after nervous system injury.

3. Movement Disorders

At this time, there is no cure for Parkinson's disease. Symptoms of Parkinson's disease are initially
treated by giving patients medications designed to stimulate the dopamine system or mimic its
controlling effect on other nerve cells. Although these medications are initially effective,
prolonged use can lead to severe dyskinesias, which are large uncontrollable movements,
hallucinations and freezing episodes.

Patients with rigidity or akinesia may benefit from micropallidotomy, while patients with tremors
may be candidates for thalamotomy. The Los Angeles Neurosurgical Institute is also the first
center on the West Coast to offer chronic deep brain stimulation (DBS). In this approach, an
electrode is placed in the focal point in the brain and stimulates the cells rather than permanently
destroy them. The surgeon can modulate the discharge, increasing or decreasing the length and
intensity of the stimulation.

In Collaboration with NeuroGeneration, a biotechnology company, the Los Angeles Neurosurgical
Institute is developing new transplant techniques for degenerative, traumatic and neoplastic
diseases of the central nervous system such as Parkinson's disease and other movement disorders.
The objective of these research efforts is to develop neural stem cell therapy and cell lines to
transplant patients at the end-stage of disease so their brain will secrete a nerve transmitter that is
deficient in the brain.

4. Alzheimer's disease

Several genes and biochemical pathways have been demonstrated to be related to Alzheimer's
disease (AD). One of the unanswered and mysterious questions is why this disease starts late in
lifetime. If mutations in some genes are the cause of Alzheimer's disease, why don't these defects
result in degenerative changes earlier? To explain that, we propose the hypothesis that expression
of several regulatory genes changes during aging which leads to the changes in the homeostasis of
neuronal specific gene regulations (regulatory networks) and makes neurons more vulnerable to
mutations and damaging external conditions. Our experimental data support this hypothesis. It has
been demonstrated that expression of many genes including genes encoding neurotrophins and
receptors for neurotrophins are changed in Alzheimer's disease. The reasons for these changes are
unknown. We obtained changes in helix-loop-helix transcription factors during aging and in AD.
Based on experimental data we hypothesize that changes in the expression of helix-loop-helix
transcription factors contribute to the changes of homeostasis of neuronal specific gene expression
and development of Alzheimer's disease. We analyze expression of these transcription factors in
AD brain and develop methods to change gene expression using different approaches including
gene therapy.

Basic Neurophysiology and Cognitive Neurosciences Laboratories

Epilepsy that cannot be controlled with medications is called "intractable" -- meaning that
disabling seizures continue to occur even though the patient has received the maximum medical
treatment. Epilepsy surgery is an effective, yet underutilized, treatment for epilepsy patients.
While only a small percentage of potential surgery candidates are referred to epilepsy surgery
centers, for many patients with epilepsy, their disability can be completely eliminated by surgical
intervention.

The Epilepsy Surgery Program at the V offers sophisticated diagnostic procedures, access to
clinical trials, pre-surgical evaluation and comprehensive treatment for childhood and adult
epilepsy.

As part of its commitment to state-of-the-art care, the Los Angeles Neurosurgical Institute
includes research efforts focused on developing new, noninvasive technologies for functional
brain mapping and seizure localization.

In addition, the Basic Neurophysiology and Cognitive Neurosciences Laboratory analyzes the
effects of chronic brain damage from epileptic activities and the degree of improvement after
seizure-free status. Researchers are also looking at the cognitive aspect of surgery and how it
affects the behavior of the patient. PET studies are conducted to study the overall metabolism
changes before and after surgery.

For More Information

The Foundation for Neural Repair is committed to be at the forefront of the neuroscience
revolution and serve as a center of research and clinical excellence for neurological disorders.

For more information about the research program, or to make a referral to the clinical program,
contact the Los Angeles Neurosurgical Institute at (800) 496-4544.