Exosome-based Nanoplatform for Ldlr mRNA Delivery in FH

NCT05043181 | Not Yet Recruiting Phase 1

• 1 other identifier: 20210817V2.0
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

mRNA therapy is a highly promising gene therapeutic strategy in the treatment of Homozygous Familial Hypercholesterolemia (HoFH). Exosomes is safe and efficient carriers for mRNA drug delivery, due to their biocompatibility, bioavailability. This first-in-human study is aimed to evaluate the safety and preliminary effectiveness of Exosome-based ldlr mRNA nanoplatform for gene therapy in HoFH.

Conditions

Familial Hypercholesterolemia

Outcome Measures

Primary Outcomes (4)

• Changes of Total Cholesterol

  mmol/L

  Changes from Baseline Total Cholesterol at Day 19

• Changes of Low-Density Lipoprotein Cholesterol

  mmol/L

  Changes from Baseline Low-Density Lipoprotein Cholesterol at Day 19

• Changes of High-Density Lipoprotein Cholesterol

  mmol/L

  Changes from Baseline High-Density Lipoprotein Cholesterol at Day 19

• Changes of Triglyceride

  mmol/L

  Changes from Baseline Triglyceride at Day 19

Secondary Outcomes (3)

• Changes of Degree of Coronary Stenosis

  Changes from Baseline Degree of Coronary Stenosis at Day 28

• Changes of Volume of Carotid Artery Plaques

  Changes from Baseline Volume of Carotid Artery Plaques at Day 28

• Changes of Stability of Carotid Artery Plaques

  Changes from Baseline Stability of Carotid Artery Plaques at Day 28

Study Arms (1)

Homozygous Familial Hypercholesterolemia

EXPERIMENTAL

Biological: Low Density Lipoprotein Receptor mRNA Exosomes

Interventions

Low Density Lipoprotein Receptor mRNA Exosomes BIOLOGICAL

The study consists of two phases: dose escalation phase and extension phase. Dose escalation phase：For the intervention of low-density lipoprotein receptor mRNA (LDLR mRNA) exosomes. A total of six dose groups are planned, with single dose of 0.044 mg/kg, 0.088 mg/kg, 0.145 mg/kg, 0.220 mg/kg, 0.295 mg/kg and 0.394 mg/kg, respectively. About 3 subjects are enrolled in each dose group. In the 0.044 mg/kg group, the second and third subjects are required to start exosome infusion treatment after the treatment of the previous subjects, and the other dose groups are not required to do this. There are three treatments in total, and the interval between each exosome treatment is 7±1 d. Extension phase: About 12 subjects are further enrolled. The subjects will receive 3 intravenous/peritoneal infusion treatment of LDLR mRNA exosomes once a week for three weeks, whose single dose is determined in the dose escalation phase.

Homozygous Familial Hypercholesterolemia

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-45, no gender limitation;
• Patients with homozygous familial hypercholesterolemia diagnosed by genetic testing.
• Understand the study and be willing to participate in the study with the informed consent signed

You may not qualify if:

• those who have severe comorbidities, including any of the following: A) unstable angina pectoris and/or congestive heart failure requiring hospitalization; B) myocardial infarction or cerebrovascular accident within the last 6 months; C) chronic obstructive pulmonary disease worsens or requires hospitalization; D) serious diseases of vascular, nervous system, blood, gastrointestinal and endocrine systems or metabolic disorders; E) autoimmune/immune deficiency diseases such as rheumatoid arthritis, acquired immune deficiency syndrome, and so on; F) malignant tumor or other chronic infection.
• those who previously received targeted drug therapy, cell therapy, gene therapy or others immunotherapy;
• those who had organ transplants in the past;
• any of the following abnormalities are found in the laboratory examination: A) blood routine examination: absolute neutrophil count (ANC) \< 1.5×109/L, or platelet (PLT) \< 50×109/L, or hemoglobin (HGB) \< 80 g/dL; B) coagulation function: prothrombin time (PT), or activated partial thrombin time (APTT), or INR \> 1.5×ULN; C) liver function: total bilirubin (TBIL) \> 2×ULN (upper limit of normal value), or alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP) \> 5×ULN; D) renal function: serum creatinine (Cr) ≥1.5×ULN, or glomerular filtration rate (GFR) \< 60 mL/min·1.73m2; E) cardiac ultrasound: left ventricular ejection fraction (LVEF) \< 50%.
• those who are known or expected to have an allergic reaction to or have a history of allergic reaction to any of the ingredients treated by this test;
• those who have a history of contrast agent allergic;
• those who have a clear history of mental disorders in the past;
• those who have a history of drug abuse or drug use;
• Pregnant or lactating women;
• Women of childbearing age and fertile men cannot take effective and adequate contraceptive measures (such as intrauterine device (IUD), condom, spermicidal gel plus condom, uterine cap, etc.) during the period of receiving the study drug and 3 months after the end of the study;
• those who participated in the clinical study of other drugs within 3 months before joining the group;
• Subjects that are not suitable to participate in this study for other reasons judged by the investigators.

Sponsors & Collaborators

• Tang-Du Hospital: lead
• Air Force Military Medical University, China: collaborator

Study Sites (1)

Tangdu Hospital, Air Force Medical University

Xi'an, Shannxi, 710038, China

Location

MeSH Terms

Conditions

Hyperlipoproteinemia Type II

Condition Hierarchy (Ancestors)

Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Lijun Yuan

  Tangdu Hospital-Air Force Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zhelong Li

CONTACT

13319189556; lzlfmmu@foxmail.com

Changyang Xing

CONTACT

13571864787; xingcy712@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the department of ultrasound diagnostics

Study Record Dates

• First Submitted: September 3, 2021
• First Posted: September 14, 2021
• Study Start: December 1, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: September 14, 2021

Record last verified: 2021-09

Locations

CN (1)