Cellular Pharmacodynamics of Small Molecules in Lysosomal Storage Disorders

• ClinicalTrials.gov Identifier: NCT03812055
• Recruitment Status: Unknown
• First Posted: January 22, 2019
• Last Update Posted: January 22, 2019
• Sponsor: Lysosomal and Rare Disorders Research and Treatment Center, Inc.
• Information provided by (Responsible Party): Lysosomal and Rare Disorders Research and Treatment Center, Inc.

Study Description

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.

Condition or disease
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 Design

• Study Type: Observational
• Estimated Enrollment: 50 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Cellular Pharmacodynamics of Small Molecules in Sanfilippo Disease(s) (MPS3) and Other Lysosomal Storage Disorders
• Actual Study Start Date: July 6, 2018
• Estimated Primary Completion Date: July 2020
• Estimated Study Completion Date: July 2020

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. Effect on enzyme activity [ Time Frame: 24 months ]
   To evaluate the effect of small molecules on level of enzyme activity in primary cells derived from patients using fluorometric enzyme assays.
2. Effect on substrate accumulation [ Time Frame: 24 months ]
   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
3. Effect on autophagy-lysosomal pathway [ Time Frame: 24 months ]
   To evaluate the effect of small molecules on autophagy-lysosomal functions in primary cells derived from patients using commercially available assays
4. Effect on mitochondrial functions [ Time Frame: 24 months ]
   To evaluate the effect of small molecules on energy metabolism and mitochondrial functions in primary cells derived from patients using commercially available assay kits
5. Effect on immune and inflammatory response [ Time Frame: 24 months ]
   Examine the immune and inflammatory response to treatment with small molecules using flow cytometry based immunophenotyping

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• 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.

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.

Contacts and Locations

Contacts

Contact: Margarita M Ivanova, PhD; 7032616220; mivanova@ldrtc.org

Contact: Uyensa Beese; 7032616220; ubeese@ldrtc.org

Locations

United States, Virginia

LDRTC; Recruiting

Fairfax, Virginia, United States, 22030

Contact: Margarita Ivanova, PhD 703-261-6220 mivanova@ldrtc.org

Contact: Ozlem M Goker-Alpan, MD 7032616220 ogokar-alpan@ldrtc.org

Principal Investigator: Ozlem Goker-Alpan, MD

Principal Investigator: Margarita M Ivanova, PhD

Sub-Investigator: Renuka Limgala, PhD

Sponsors and Collaborators

Lysosomal and Rare Disorders Research and Treatment Center, Inc.

Investigators

• Principal Investigator: Margarita M Ivanova, PhD; LDRTC
• Principal Investigator: Ozlem Goker-Alpan, MD; LDRTC
• Principal Investigator: Renuka Limgala, PhD; LDRTC

More Information

Additional Information:

Institute website for more details 

• Responsible Party: Lysosomal and Rare Disorders Research and Treatment Center, Inc.
• ClinicalTrials.gov Identifier: NCT03812055
• Other Study ID Numbers: 18-LDRTC-02
• First Posted: January 22, 2019
• Last Update Posted: January 22, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lysosomal Storage Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases