Providing new hope to families facing the
debilitating aspects of lysosomal storage diseases.
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Since 2007, the New Hope Research Foundation has coordinated and funded numerous research
projects investigating options for treating the central nervous system (CNS) aspects of lysosomal
storage diseases.  The focus of these studies have been finding treatments for GM2 gangliosidosis, a
disease that primarily affects the CNS.  It is the hope that the discovery of general methods for
treating this disease could be utilized in the future for other diseases that affect the CNS.

Pharmacological Chaperone Therapy
Early studies funded by the Foundation investigated a small molecule drug, called pyrimethamine,
which is known to cross the blood brain barrier (BBB) and enter the brain,  This oral drug has been
by the US Food and Drug Administration for over a half century for the treatment of malaria
and toxoplasmosis
.  It has been recently shown in the laboratory to aid in the stability of the
hexosaminidase enzyme, which is needed to break down GM2 ganglioside.  Clinical studies, funded by
the New Hope Research Foundation, have shown that pyrimethamine serves as a pharmacological
chaperone for the hexosaminidase enzyme and that pyrimethamine is thereby able to i
ncrease the
level of the enzyme in Adult Tay-Sachs disease patients that express an unstable form of this
enzyme.  More information on the pyrimethamine clinical study results was published by
Clarke et al.
and in a case study presented by Keimel and Charnas (2009) and by Keimel (2010).

Gene Therapy
Gene therapy has the greatest potential for curing GM2 gangliosidosis and other lysosomal storage
diseases that affect the CNS.  Two major challenges associated with gene therapy relate to the need
for adequately distributing the gene vector throughout the CNS and in avoiding an immune response
to the protein expressed by the gene vector.  The gene therapy research
now being conducted by the
Foundation is focused on responding to these two challenges.

Biodistribution:  Early gene therapy clinical studies used a method of directly injecting the vector
into the brain tissue, but the vector does not distribute very far from
 the site of injection and the
volume of tissue transduced with this method is extremely limited.  This method is only practical in
small animal brains.  The New Hope Research Foundation has focused its research on gene transfer
delivery methods that will result in broad delivery of the gene vector throughout the CNS.  The
Foundation has identified methods for gene delivery, and is currently conducting investigations to
delineate the vector distribution within the body, and in particular, the CNS.  A future research project
to evaluate these delivery methods in large animals is planned.

HexM:  Research funded by the Foundation has also resulted in the development of a new enzyme,
called HexM, licensed to the Foundation.  The advantage of HexM is that the complete gene can be
packaged in one small adeno-associated virus (AAV) capsid.  Incorporating the complete genetic
material into a single small package has been shown to enhance the CNS biodistribution and also
increase the efficiency of the vector.  

Extensive investigations have been completed that confirm the function of the new variant
hexosaminidase enzyme, HexM, in effectively degrading the GM2 ganglioside within cell culture
Tropak et al., 2016 and Tropak et al., Supplement, 2016).  The initial in vivo gene therapy research
using this new enzyme in neonatal mice was presented at the 2015 annual meeting of the American
Society for Gene and Cell Therapy (ASGCT) by
Karumuthil Melethil et al., 2015, and Osmon et al.,
2015.  It was also summarized in a poster presented by Keimel et al., 2015, at the annual meeting of
the Institute for Engineering in Medicine.  This research not only established that the enzyme is
effective in degrading GM2 ganglioside in mouse models of Tay-Sachs and Sandhoff disease, but
also demonstrated that the treatment allowed significant improvements in both the behavioral testing
and longevity of the diseased mice.  Details of these studies have been published by
Melethil et al., 2016
(and Karumuthil Melethil et al., Supplement, 2016), and by Osmon et al., 2016.  
The gene vector expressing HexM has also been shown to be effective after treating
adult mice with
either an intravenous injection (
Osmon et al., ASGCT 2016) or by an injection into cerebrospinal fluid
Thompson et al., ASGCT 2016).  A key result from these studies is the evidence that the AAV vector
is able to cross the mature blood-brain-barrier and transduce cells within the CNS.  These studies also
showed that the gene transfer resulted in significantly improved behavioral performance and
increased longevity when the therapy is injected into adult mice.

Immune Tolerance:  The human immune system naturally responds with strong defenses to the
invasion of "foreign" particles.  Critical to this function is the ability to distinguish these foreign
invaders from the body's own molecules and cells, referred to as "self".  
It is anticipated that patients
with mutations resulting in no
expression of a hexosaminidase gene are expected  to have an immune
following the introduction of the enzyme through enzyme replacement therapy (ERT) or to
the expression of the enzyme following gene transfer.  
The Foundation is currently funding the
development  of assays that allow the measurement of anti-HexM antibodies and HexM specific T-
cells, which could proliferate following a gene therapy.  The research being funded by the Foundation
is currently assessing this immune response in Tay-Sachs and Sandhoff mice in preparation for
evaluating methods for inducing immune tolerance towards the HexM enzyme.

The New Hope Research Foundation is generally requesting additional proposals (See Grants) that
support research efforts that will lead to the creation of a gene therapy for GM2 gangliosidosis.  The
most recent requests for proposals can be found at the bottom of the following list:

  • Beta-hexosaminidase A cross-species heterodimer formation
    The major goal of this study is to characterize the affinity of forming a heterodimer with the beta
    subunit found in lab animals and the human alpha subunit of beta-hexosaminidase A.  Prior
    gene therapy studies in beta-hexosaminidase A deficient animals using only the human gene
    for the alpha sub-unit need to be interpreted considering the affinity of the monomers from the
    two species.  (Initial grant awarded - 2007)

  • Mechanisms of enhancing expression of beta-hexosaminidase A
    Calcium channel blockers (e.g., diltiazem or verapamil) have been shown to improve the
    expression of some lysosomal enzymes.  The goal of this project is to determine whether
    calcium channel blockers might be synergistic with pharmacological chaperone therapy (e.g.,
    pyrimethamine) in the treatment of Adult Tay Sachs Diseases.  (Initial grant awarded - 2008)

  • Historical control group for a gene therapy trial on infantile Tay-Sachs
    The goal of this project is to define the natural progression and complications associated with
    infantile Tay-Sachs disease so that it might be used as a historical control group for a future
    gene therapy clinical study.  (Initial grant awarded - 2008)

  • Self-complementary adeno associated virus (scAAV) vector
    The goal of this project is to develop a scAAV vector with the human beta-hexosaminidase A
    alpha subunit transgene.  Broad distribution of a gene therapy vector throughout the human
    brain will require a highly efficient vector.  As the average number of viral particles entering
    individual cells is reduced with the broad vector distribution, the probability of annealling two
    individual strands will also be reduced.  The self-complementary DNA eliminates the need to
    form a dual strand after the vector enters the cell.  Self complementary AAV vectors have been
    shown to be more effective when delivered in low concentrations.  The vector is also to use a
    promoter that provides long-term transduction in human neurons and glia cells while keeping
    the total DNA to a size that permits good AAV production yields.    (Multiple grants awarded -
    2011 thru 2012)

  • In cellulo Characterization of HexM
    This project is to define and characterize the activity of  the variant hexosaminidase enzyme,
    HexM, in cellulo.  (Multiple grants awarded - 2011 thru 2013)

  • Self-complementary AAV Vector Development and In vivo Efficacy of HexM in Mouse
    Models of GM2 Gangliosidosis
    This project is to develop a self-complementary AAV vector containing a ubiquitous promoter
    and the HEXM transgene.  The effectiveness of the vector is to be assess using minimally
    invasive injections of the vector in neonatal and adult Tay-Sachs and Sandhoff mice.  (Multiple
    grants awarded - 2013 thru 2014)

  • Immune Response of Expressed HexM in Animal Models
    This project is to develop assays for measuring levels of anti-HexM antibodies and HexM
    specific T-cells and to measure these levels following intravenous delivery of a HEXM vector in
    mouse models of GM2 gangliosidosis.  (Multiple grants awarded - 2015 thru 2016)

  • Induction of Immune Tolerance towards HexM
    Patients lacking expression of a hexosaminidase gene are expected  to have an immune
    response to the introduction of the enzyme through either enzyme replacement therapy (ERT)
    or  to the expression of the enzyme following gene transfer.  This project is to propose methods
    for inducing immune tolerance towards HexM and  evaluate the effectiveness of the methods in
    animal models of GM2 gangliosidosis.  (Active proposal request)

  • Clinical assay of GM2 ganglioside in leukocytes and cerebrospinal fluid
    Only small increases in the beta-hexosaminidase A enzyme expression may result in clinically
    significant reductions in GM2 storage material, and therefore, a more clinically relevant
    biomarker of therapy success should be based on the actual substrate reduction.  The goal of
    this project is to develop a GM2 assay with adequate controls to allow accurate quantitative
    comparisons over the course of a gene therapy clinical study.   (Active proposal request)

  • Methods for broadly delivering AAV vectors within the CNS of large animals
    Lysosomal storage diseases affect broad regions within the central nervous system (CNS), and
    it is assumed that an effective therapy must be similarly distributed.  A method for delivering
    AAV vectors is therefore needed that will result in broad distribution of the vector and the
    expressed enzyme within the CNS.  The goal of this project is to develop and evaluate methods
    in large animal models that could be safely applied to patients with lysosomal storage diseases.  
    (Active proposal request)

  • Gene Therapy Clinical Trial Development
    This project is to develop  and manage human clinical studies for gene therapy in patients with
    known genetic mutations causing Tay-Sachs or Sandhoff disease. (Active proposal request)