Clinical trial NCT03812055: Cellular Pharmacodynamics of Small Molecules in Lysosomal Storage Disorders
Official title: Cellular Pharmacodynamics of Small Molecules in Sanfilippo Disease(s) (MPS3) and Other Lysosomal Storage Disorders
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Lysosomal Storage Diseases
Lead sponsor: Lysosomal and Rare Disorders Research and Treatment Center, Inc.
Sponsor class: OTHER
First posted: 2019-01-22
Enrollment: 50
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients diagnosed or suspected of having a lysosomal storage disorder and family members of diagnosed patients will be recruited. Informed consent will be obtained prior to the execution of any research procedures.

Brief summary: The purpose of this study is to evaluate the effect of small molecule therapy in primary cells derived from patients with lysosomal storage disease. The study will focus 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Effect on enzyme activity
timeFrame: 24 months
measure: Effect on substrate accumulation
timeFrame: 24 months
measure: Effect on autophagy-lysosomal pathway
timeFrame: 24 months
measure: Effect on mitochondrial functions
timeFrame: 24 months
measure: Effect on immune and inflammatory response
timeFrame: 24 months
Secondary outcomes:
Other outcomes:
Locations:
city: Fairfax
country: United States
facility: LDRTC
state: Virginia
Study officials:
affiliation: LDRTC
name: Margarita M Ivanova, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: LDRTC
name: Ozlem Goker-Alpan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: LDRTC
name: Renuka Limgala, PhD
role: PRINCIPAL_INVESTIGATOR
References: