G(M2) Ganglioside Clinical Trial
Official title:
A Dose-Escalated, Double-Blind, Placebo-Controlled, Randomized Phase I Clinical Trial of Pyrimethamine in Patients Affected With Chronic GM2 Gangliosidosis (Tay-Sachs or Sandhoff Variants)
Adult Tay-Sachs disease and Sandhoff diseases are caused by deficiency of an enzyme called
β-hexosaminidase A, or Hex A in short. This enzyme is located in a particular cellular
component, called lysosomes, inside the brain cells. The reason that Hex A of patients with
Adult Tay-Sachs disease or Sandhoff disease is deficient is because this enzyme had gone
through mutation, resulting in it not working very well. In healthy people, Hex A
efficiently breaks down GM2-ganglioside, which is a by-product from cells of our body.
However, patients with Adult Tay-Sachs disease or Sandhoff disease cannot efficiently break
down GM2-ganglioside in the body. Therefore, these patients have high levels of this
by-product in the brain cells, which causes the brain to be unable to function normally.
There is a drug called Pyrimethamine. This drug is used by doctors to treat specific types
of infections called malaria and toxoplasmosis. Our laboratory test tube studies have shown
that Pyrimethamine can help the Hex A enzyme to function in a normal manner. If Hex A can
function normally in presence of Pyrimethamine, this drug should be able restore the brain
malfunction of these patients since Hex A can now efficiently break down GM2-ganglioside
with Pyrimethamine treatment.
Although results from laboratory test tube studies are promising and Pyrimethamine should
theoretically restore brain function of these patients, we do not know if Pyrimethamine is
safe or if it would actually work in patients. This study is the first study (a Phase I
study) of testing Pyrimethamine to treat Adult Tay-Sachs and Sandhoff diseases. The
objective of this study is to see if Pyrimethamine is safe in these patients and to see if
it can restore the brain function of these patients.
Adult Tay-Sachs (TSD) and Sandhoff disease (SD) result from a deficiency of lysosomal
heterodimeric β-hexosaminidase A (Hex A, αβ). These disorders are characterized by
progressive neurological deterioration that mainly affects motor, cerebral and
spinocerebellar function. They affect fewer than 1000 people in the United States. There is
no effective treatment for these diseases.
Substantial evidence supports a disease model for TSD and SD which attributes pathology to
decreased or absent Hex A levels in neuronal lysosomes of the brain. The problem in GM2 -
gangliosidosis is the inability of the cell to metabolize GM2 gangliosides. When the
residual activity of Hex A falls below a critical threshold level, GM2 ganglioside influx
into the lysosome (the site of Hex A activity) exceeds the degradation rate and excess
substrate continuously accumulates. Consequently, the lysosomes increase in size and number,
giving rise to a storage disease.
The majority of the mutations in Hex A affect the ability of the enzyme to obtain and/or
retain its native 3-dimensional fold in the endoplasmic reticulum (ER) where intracellular
quality control is performed to retain and degrade defective enzymes. Pharmacological
chaperones (PC)s are small molecules that can stabilize the native conformation of a mutant
enzyme in the ER and allow it to escape the ER's quality control system and its associated
degradation pathway (ERAD). PCs have the potential to act as drugs when they can stabilize
the native conformation of a mutant enzyme.
In 2006 ExSAR applied for orphan drug designation from the FDA for Pyrimethamine
(Pyrimethamine) for the treatment of patients affected with late-onset GM2-gangliosidosis.
The application is pending the positive outcome of clinical trials. Pyrimethamine is an
FDA-approved drug which readily passes the bloodbrain barrier (BBB). It is currently used to
treat malaria and toxoplasmosis. Our in vitro cell-based studies with fibroblasts from these
patients show that Pyrimethamine can function as a PC for Hex A and raise intracellular Hex
A levels. Our hypothesis is that Pyrimethamine administered to adult TSD and SD patients can
improve neurological function and health.
The over objective of the project is to assess the safety and tolerability of the drug. We
first conduct a Phase I trial, which is the current study, using Pyrimethamine to treat
patients affected with GM2-gangliosidosis. Hex A and B (αβ) activities in plasma and
peripheral blood leukocytes will also be measured. The working hypotheses of the Phase I
trial are that Pyrimethamine administered according to the regimen of the trial will be
tolerated and safe and result in increased Hex A levels in blood and brain.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)