Providing new hope to families facing the
debilitating aspects of lysosomal storage diseases.
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Today, Enzyme Replacement Therapy (ERT) has become the clinical gold standard for treating
lysosomal storage diseases.  Unfortunately, the large lysosomal enzymes being intravenously infused
do not cross the blood brain barrier, and no benefit has been observed in treating the central nervous
system aspects of these diseases.  To ethically achieve further advancements in treating lysosomal
storage diseases, the CNS aspects of these diseases will need to be addressed.

There are four therapeutic concepts that are currently being explored to address the CNS aspects of
  •    Enzyme Replacement Therapy (ERT)
  •    Substrate Reduction Therapy (SRT)
  •    Pharmacological (small molecule) Chaperone Therapy
  •    Gene Therapy

For ERT to be effective in treating the CNS, a mechanism will be required for delivering the enzymes
across the blood brain barrier.   In 1978, a case report described the repeated lumbar intrathecal
injections of hexosaminidase A enzyme into two young infants.  Both subsequently died from the
disease.  (
von Specht 1978)   The report concluded that this form of enzyme administration was
ineffective in reaching the brain and perhaps served to discourage further investigation of this
concept for many years.  Two possible limitations of treating these infants were the amount of enzyme
reaching the brain from the lower spine and the degree of enzyme endocytosis and intracellular
transport to the lysosomes.   Since this case report was written, a much better understanding has
evolved in the trafficking of lysosomal enzymes using the mannose-6-phosphate receptors (
2006).  While other means for enhancing endocytosis have been demonstrated (Dobrenis 1992), the
conjugation of enzymes with mannose-6-phosphate is widely used today in market-released ERT.  
Also advanced since the case report, is the improved understanding of cerebral spinal fluid flow
patterns.  A recent study on Mucopolysaccharidosis type I model dogs using bolus injections of
laronidase (83 KD) into the intrathecal cisterna magna location showed significant reduction in storage
material throughout the brain. (
Kakkis 2004)   The recent comparison of the distribution of this enzyme
using bolus and continuous infusion of the enzyme into the cisterna magna has provided further
insight into the ERT therapeutic options for the CNS.  (
Keimel 2006)

Substrate Reduction Therapy for the treatment of Gaucher disease has been approved by the US
Food and Drug Administration since 2003.  This treatment (miglustat, brand named Zavesca) reduces
the synthesis of glucocerebroside (see
Figure 1) in order to offset the reduced ability to catabolize this
substance in Gaucher disease patients. (
Lachmann 2001)  Because this therapy utilizes a small
molecule and is believed to pass through the blood-brain barrier, it is now also being clinically
investigated for a number of the downstream glycosphingolipid related diseases including Tay Sachs.  

For a number of the Hexosamindase A mutations that cause the adult onset forms of GM2
Gangliosidosis, the reduced enzyme activity is believed to be caused by the misfolding of the enzyme
in the endoplasmic reticulum leading to limited trafficking to the lysosomes.  It has been observed that
certain mechanism-based inhibitors of Hexosaminidase A will decrease the retention of enzyme in the
endoplasmic reticulum and provide an overall increase in the total activity level of the enzyme within
the lysosome.  For the adult onset form of GM2 Gangliosidosis with the homozygous αG269S mutation
a three-fold increase in Hexosamindase A activity has been observed. (
Lemieux 2006)  This approach
may provide a unique solution for patients with the particular mutations that benefit from this
“chaperone” concept.  Go to the
Research section to learn more on clinical studies funded by the New
Hope Research Foundation on a pharmacological chaperone for treating GM2 gangliosidosis.

Gene Therapy for GM2 Gangliosidosis