Cellular Pharmacodynamics of Small Molecules in Lysosomal Storage Disorders

Cellular Pharmacodynamics of Small Molecules in Sanfilippo Disease(s) (MPS3) and Other Lysosomal Storage Disorders

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.

Study Overview

• Status: Unknown
• Conditions: Lysosomal Storage Diseases

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.

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: Margarita M Ivanova, PhD; Phone Number: 7032616220; Email: mivanova@ldrtc.org
• Study Contact Backup: Name: Uyensa Beese; Phone Number: 7032616220; Email: ubeese@ldrtc.org

Study Locations

• United States
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Recruiting
      • LDRTC
      • Contact: Margarita Ivanova, PhD; Phone Number: 703-261-6220; Email: mivanova@ldrtc.org
      • Contact: Ozlem M Goker-Alpan, MD; Phone Number: 7032616220; Email: ogokar-alpan@ldrtc.org
      • Principal Investigator: Margarita M Ivanova, PhD
      • Sub-Investigator: Renuka Limgala, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
LSD; Subjects diagnosed or suspected to have any of the following lysosomal storage diseases: Gaucher disease, Fabry disease, Pompe disease, Mucopolysaccharidoses.
Control; Subjects with no known lysosomal storage disorder

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on enzyme activity	To evaluate the effect of small molecules on level of enzyme activity in primary cells derived from patients using fluorometric enzyme assays.	24 months
Effect on substrate accumulation	To evaluate the effect of small molecules on heparin sulfate accumulation and substrate accumulation in primary cells derived from patients using techniques like ELISA and mass spectrometry	24 months
Effect on autophagy-lysosomal pathway	To evaluate the effect of small molecules on autophagy-lysosomal functions in primary cells derived from patients using commercially available assays	24 months
Effect on mitochondrial functions	To evaluate the effect of small molecules on energy metabolism and mitochondrial functions in primary cells derived from patients using commercially available assay kits	24 months
Effect on immune and inflammatory response	Examine the immune and inflammatory response to treatment with small molecules using flow cytometry based immunophenotyping	24 months

Collaborators and Investigators

• Sponsor: Lysosomal and Rare Disorders Research and Treatment Center, Inc.
• Investigators: Principal Investigator: Margarita M Ivanova, PhD, LDRTC; Principal Investigator: Ozlem Goker-Alpan, MD, LDRTC

Publications and helpful links

Helpful Links

• Institute website for more details

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2018
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): July 1, 2020

Study Registration Dates

• First Submitted: January 18, 2019
• First Submitted That Met QC Criteria: January 18, 2019
• First Posted (Actual): January 22, 2019

Study Record Updates

• Last Update Posted (Actual): January 22, 2019
• Last Update Submitted That Met QC Criteria: January 18, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases
• Other Study ID Numbers: 18-LDRTC-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No