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Sustained TPP1 Enzyme Delivery for the Treatment of CLN2 Disease Using Genetically Modified
Autologous Stem Cells (CLN2)
Principal Investigator: Rebecca Whiting, Ph.D., The University of Missouri, $55,000, Noah’s HopeHope4Bridget, Drew’s Hope
We will test an innovative method for sustained delivery of TPP1 enzyme to the brain and eye in a dog
model of CLN2 disease. To determine whether this approach can be used to treat children with CLN2,
we will isolate cells from a CLN2 dog’s bone marrow and genetically modify them to produce large
amounts of the enzyme. These cells will then be injected into the dog's eye and into the fluid that
surrounds the brain, where we expect they will remain and secrete the TPP1 enzyme, which will then be
used by these tissues to function normally. We expect that a single injection of cells into the eye and the
brain will prevent, or at least slow, the progression of CLN2 symptoms. If these studies are successful in
the dog model, clinical trials will be planned to test this treatment approach in children with CLN2
disease.
mTOR-Independent Lysosomal Enhancement for the Treatment of Neuronal Ceroid Lipofuscinoses
(CLN3, CLN6, CLN8)
Principal Investigator: Marco Sardiello Ph.D., Baylor College of Medicine, $30,000, BDSRA
Many neurodegenerative diseases share as a common cellular feature the accumulation of undigested
material, which in many instances has been proven to play a causative role in the pathogenesis of the
disease. Pathological accumulation of undigested material is often the result of an overwhelmed cellular
degradative system, which can be due either to genetic defects that affect the function of lysosomal and
autophagy pathways (e.g., lysosomal storage disorders), or to different causes such as the abnormal
generation of aggregation-prone proteins (e.g., Alzheimer’s, Parkinson’s and Huntington’s diseases). We
and others have provided proof-of-principle evidence that activation of lysosomal pathways may be an
effective strategy to ameliorate disease phenotypes in animal models of these neurodegenerative
diseases. The overall goal of this project is to use pharmacological activation of lysosomal pathways—
obtained by repositioning an FDA-approved drug—to counteract disease progression in a mouse model
of Neuronal Ceroid Lipofuscinosis. We will also test how this strategy can be extended to the whole
group of the NCLs by cell-centered studies. We have strong evidence that lysosomal enhancement
mediated by activation of TFEB, a master regulator of autophagic-lysosomal pathways, is of benefit in
mouse models of Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) and Sanfilippo Syndrome Type IIIB. We
have now identified a new signaling pathway that (1) leads to the activation of TFEB in the brain, (2) is
pharmacologically actionable with small drugs that are currently being tested in clinical trials, and (3) is
independent of the mTOR signaling. Our preliminary data show that the pathways activated by TFEB
have the potential to counteract neurodegeneration in a plethora of diseases characterized by the
storage of undegraded material. Thus, results from this project could benefit the whole group of
Neuronal Ceroid Lipofuscinoses (NCLs) and could rapidly lead to translation.
Link between “danger signals” and inflammasome activation in the pathogenesis of Juvenile Batten
Disease (CLN3)
Principal Investigator: Tammy Kielian, Ph.D., The University of Nebraska Medical Center, $40,000, BDSRA
Juvenile Batten Disease is a fatal neurodegenerative disorder with no cure. Disease symptoms appear
between 5-10 years of age, beginning with blindness and progressing to seizures, motor and cognitive
decline, and premature death (late teens to early 20s). Caspase-1 is an enzyme that can induce
inflammatory cell death and our laboratory is the first to discover that caspase-1 enzyme activity is
inappropriately active in brain regions where eventual neuron loss occurs in JNCL. This proposal will
explore the molecular signals within neurons, microglia, and astrocytes that are responsible for aberrant
caspase-1 activity in the context of CLN3 mutation. Our preliminary in vivo studies support a key role for
caspase-1 in Juvenile Batten Disease progression and as a promising therapeutic target to prevent/delay
neuron loss. A better understanding of the molecular triggers within neurons and glia that lead to
inappropriate caspase-1 activity may provide a means to regulate enzyme dysfunction and improve
neuronal survival.
Cross-correction in CLN6 Batten disease (CLN6)
Principal Investigator: Stephanie Hughes, Ph.D., University of Otago, New Zealand, $40,000, BDSRA
Batten disease is a group of brain diseases that usually present in children and show clinical symptoms
similar to Alzheimer's and Parkinson's disease with epilepsy and blindness. There is currently no cure for
any form, although several preclinical and clinical trials are showing promise. Gene therapy is a method
to deliver a functional version of the mutant gene directly to the cells in the brain that need it. In some
forms of Batten disease this is relatively easy, when the missing gene product is a soluble protein that
can spread from cell to cell; a process known as cross-correction. In other forms including CLN3 and
CLN6, where the missing gene product is a membrane protein, it is assumed that a complete cure would
require each cell in the brain to directly receive the gene therapy. We have evidence that crosscorrection is possible in CLN6 Batten disease, and that using a novel gene therapy strategy we can make
these challenging forms easier to treat. This proposal will test the idea that CLN6 disease can be treated
by cross-correction. Demonstrating that our method works would provide a rapid path towards
translation since the cross-correctable forms (including CLN2) are already in clinical trials.
Determining the neuronal specific mechanisms of CLN3 in Juvenile Neuronal Ceroid Lipofuscinoses
Principal Investigator: Jacob Cain Ph.D., Sanford Research, $45,000, BDSRA
Batten Disease is a neurodegenerative disease caused by a lysosomal storage disorder, which results in
the premature death. The juvenile form of Batten Disease (JNCL) is the result of a mutation in the CLN3
gene. The CLN3 gene codes for a protein that is expressed in many different cell types, including
neurons, however its function, specifically in neurons, is largely unknown. This project focuses on
identifying the role of CLN3 in neurons using two novel approaches. The first uses mice engineered and
bred to recapitulate the most common CLN3 mutation in neurons only. Previous studies looking at CLN3
use mice which have the mutation in all of their cells. By selectively targeting just the neurons, this study
will identify neuron specific mechanisms of CLN3. The second approach uses a technique called BioID to
identify proteins that interact with CLN3. BioID is a biotin ligase, an enzyme which glues a biotin tag onto
nearby proteins. By fusing BioID to CLN3 and expressing it in neurons, we can tag and identify proteins
which interact with CLN3. Together, these approaches will help the Batten research community better
understand the neuron specific mechanisms driven by CLN3 and identify potential therapeutic targets
for the treatment of JNCL.
Advanced diffusion MRI in Batten disease (CLN3): white matter microstructure and brain connectivity
(CLN3)
Principal Investigator: Taina Autti, Ph.D., University of Helsinki, Finland, $50,000, BDSRA and Thisbe and
Noah Scott Foundation
Juvenile neuronal ceroid lipofuscinosis (CLN3) is an inherited, autosomal recessive, progressive,
neurodegenerative disorder of childhood. It belongs to the lysosomal storage diseases, and its incidence
in Scandinavia is high, 2.0-7.0 per 100,000 births. The symptoms include loss of vision, epileptic seizures,
psychiatric problems and loss of cognitive and motor functions.
Previous brain magnetic resonance imaging (MRI) studies have shown progressive cerebellar and
cerebral changes in NCL. The signal intensity abnormalities have been observed in the white matter,
especially in the periventricular regions and internal capsules, as well as in the thalami in most childhood
forms of NCL.
We have previously published 32 articles concerning imaging in NCLs. We found strikingly focal
alterations in the brains of CLN3 patients: the gray matter volume was significantly decreased in the
dorsomedial part of the thalami and the volume of the white matter was significantly decreased in the
corona radiata. This suggests that the thalamocortical neural tracts may have a significant role in the
pathogenesis of CLN3.
Based on these previous studies, we will now investigate white matter microstructure and brain
connectivity with the newest noninvasive diffusion MRI methods in 30 individuals with CLN3 and 30 age
and sex matched healthy control subjects.
We will investigate the neural tracts both locally and globally with several methods. Advanced
biophysical models will be used. First, the voxel-wise differences will be investigated, and then based on
the findings several chosen tracts will be investigated separately. Furthermore, we will use a new
approach, in which brain networks are reconstructed. Both local and global properties such as efficiency
of the network can be investigated with mathematical methods. Imaging studies are crucial in
understanding the pathogenesis of the disease, which is very important in the development of new
therapies and their evaluation.