Cellular Pharmacodynamics of Small Molecules in Lysosomal Storage Disorders

Lysosomal storage diseases (LSD) often cause severe disability and have a devastating effect
on quality of life. The current standard of care of a majority of LSD is enzyme replacement
therapy (ERT). ERT, however, becomes less effective during the advanced stages of a disease.
Another therapy is substrate reduction therapy (SRT). For example, SRT therapy for Gaucher
disease with small molecules acts on ceramide synthesis pathway by decreasing production of
the substrate. But, none of the above therapies are effective for treatment of a neuropathic
form of LSD. Neurodegenerative changes in the central nervous system are a major problem in
Sanfilippo disease. They cause severe disability and behavioral disturbance. This is the main
reason for the absence of therapeutic options for MPS3 (Sanfilippo) patients. The future of
neuropathic form of LSD therapy may lie in small molecules acting as agents for
enzyme-enhancement therapy (EET). EET is based on the ability of small molecules to fold the
misfolded mutant enzyme, activate autophagy-lysosomal pathways or mitochondrial function.
This treatment approach has the potential to cross the CNS and carries the potential to treat
the neurological symptoms of Sanfilippo disease or other types of LSD.

The purpose of this study will evaluate the effect of small molecule therapy in primary cells
derived from patients with lysosomal storage disease. The study will be focused on activity
of small molecules, in terms of measurements enzymes activity and level of substrates
accumulations. Also, the effects of small molecules on cell function, including
autophagy-lysosomal pathways, metabolism, mitochondrial function and immune reaction will be
investigated.

Inclusion Criteria:

Subjects with

1. confirmed diagnosis of any lysosomal storage disorder

2. family members with history of lysosomal storage disorders

Exclusion Criteria:

Subjects excluded from the study include those who:

1. present with severe cognitive deficits impairing decision making

2. are unable to or for whom it is medically unsafe to withdraw from their current
medications, such as subjects on SSRI s and other psychoactive drugs. The subjects on
SSRIs may be included in the study only with an approval from the prescribing
physician to discontinue their medications temporarily for the study.

3. are pregnant or nursing. All women of child bearing potential will undergo a pregnancy
test.

4. have a history of neurologic conditions such as stroke or any focal brain lesion that
may result in parkinonian manifestations. Individuals with such MRI findings will be
excluded from the study.