Familial HypercholesterolemiaPhase 1ENDFHNCT05043181
Exosome-based Nanoplatform for Ldlr mRNA Delivery in FH
A Phase 1 study testing Low Density Lipoprotein Receptor mRNA Exosomes in people with Familial Hypercholesterolemia, run by Tang-Du Hospital at 1 site in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 45 years
- Conditions the study is for
- Familial Hypercholesterolemia
- What is being tested?
- Low Density Lipoprotein Receptor mRNA Exosomes
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteChina
- Study dates
- Dec 2021to Dec 2026
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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;
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- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
China1 site
Tangdu Hospital, Air Force Medical University
Xi'an, Shannxi, 710038
About this study
Official title: Exosome-based Nanoplatform for Ldlr mRNA Delivery in Familial Hypercholesterolemia
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.
Read the detailed description
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by severely elevated plasma low-density lipoprotein (LDL) cholesterol (LDL-C) and premature coronary heart disease. Most of FH patients (about 95% of cases) are attributed to functional loss mutation of the LDL receptor (LDLR) gene. The prevalence of the heterozygous mutations in LDLR has been estimated at 1 in 200 to 1 in 500 in the population, and the homozygous form in 1 in 100000 individuals. As a key lipoprotein receptor on the surface of hepatocyte, the LDLR is critical for liver clearing LDL-C from the circulation. By endocytosis and further processing of the LDL-C, LDLR is responsible for removing most excess LDL-C from the serum, and there are no substitutes in vivo. These heterozygotes (HeFH) typically have twice the normal plasma LDL levels and cardiovascular diseases at an earlier age. Homozygous individuals (HoFH) face much higher LDL-C levels and often die before the age of 20 years if untreated. Although existing therapeutics, such as statins, ezetimibe and PCSK9 inhibitors, have some beneficial effects on HeFH, few drugs have therapeutic effects on HoFH even at high-doses. Lipid apheresis and liver transplantation are the current clinical managements to reduce the LDL-C level, while gene therapy holds the promise.
Exosomes are small intracellular vesicles ranging in 30-150 nm size and have an important role in cell-cell communication. Many studies show that exosome can efficiently deliver cargos, such as mRNA, miRNA and even plasmid DNA, to target cells, emerging as a promising therapeutic carrier for gene therapy. Compared with virus, exosomes, as "natural nanoparticles", are easy to handle, non-cytotoxic and non-immunogenic. It is thus promising to develop exosome-based LDLR-gene delivery strategy and explore the therapeutic effects on HoFH.
In this study, an Ldlr-expressing virus vector will be constructed to generate Ldlr mRNA-enriched exosomes. To meet the standards of clinical trials, we will use the GMP-grade compliant normal donor bone marrow-derived MSCs to produce exosomes. Exosomes will be enriched by filtration and ultracentrifugation, and then normalized by Nanosight, Electron microscopy and key exosomes biomarkers. In order to ensure the safety of patients, we plan to inject exosomes through abdominal puncture under ultrasound guidance, and purchase medical insurance for patients. This first-in-human study is aimed to evaluate the safety of this exosome product for gene therapy and preliminary evidence of efficacy using plasma LDL-C levels as a surrogate biomarker. The study is promising to provide a new therapeutic approach for the treatment of Homozygous Familial Hypercholesterolemia patients.
- Conditions
- Familial Hypercholesterolemia
- Being tested
- Low Density Lipoprotein Receptor mRNA Exosomes
- Medical subject headings
- Hyperlipoproteinemia Type II
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low Density Lipoprotein Receptor mRNA ExosomesBiological
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.
| Study group | Role | What they receive |
|---|---|---|
| Homozygous Familial Hypercholesterolemia | Experimental | Not described Receives: Biological: Low Density Lipoprotein Receptor mRNA Exosomes |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes of Total Cholesterol
mmol/L
Measured: Changes from Baseline Total Cholesterol at Day 19
Changes of Low-Density Lipoprotein Cholesterol
mmol/L
Measured: Changes from Baseline Low-Density Lipoprotein Cholesterol at Day 19
Changes of High-Density Lipoprotein Cholesterol
mmol/L
Measured: Changes from Baseline High-Density Lipoprotein Cholesterol at Day 19
Changes of Triglyceride
mmol/L
Measured: Changes from Baseline Triglyceride at Day 19
Secondary outcomes (3)
Changes of Degree of Coronary Stenosis
% determined by coronary CT
Measured: Changes from Baseline Degree of Coronary Stenosis at Day 28
Changes of Volume of Carotid Artery Plaques
cm3 determined by ultrasound
Measured: Changes from Baseline Volume of Carotid Artery Plaques at Day 28
Changes of Stability of Carotid Artery Plaques
Grade I, II, III determined by ultrasound
Measured: Changes from Baseline Stability of Carotid Artery Plaques at Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Sep 2021
- Study startDec 2021 (estimated)
- Primary completionDec 2026 (estimated)
- Study completionDec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Familial HypercholesterolemiaStudies of the same condition, open and under way.
- More trials run by Tang-Du HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Tang-Du Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Air Force Military Medical University, China
- Responsible party
- Principal investigator, Lijun Yuan, MD, PhD, Tang-Du Hospital
- Investigators
- Lijun Yuan, Principal investigator, The Second Affiliated Hospital of Air Force Military Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05043181
- Sponsor's protocol ID
- 20210817V2.0
- Acronym
- ENDFH
- Status last verified
- Sep 2021
- First submitted
- 3 Sep 2021
- Last updated
- 14 Sep 2021
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exosome-based Nanoplatform for Ldlr mRNA Delivery in Familial Hypercholesterolemia
- ClinicalTrials.gov ID
- NCT05043181
- Acronym / sponsor ID
- ENDFH / 20210817V2.0
- Conditions
- Familial Hypercholesterolemia
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Tang-Du HospitalUniversity, hospital or other
- Collaborators
- Air Force Military Medical University, China
- Study start
- Dec 2021 (estimated)
- Primary completion
- Dec 2026 (estimated)
- Study completion
- Dec 2026 (estimated)
- First posted
- 14 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by severely elevated plasma low-density lipoprotein (LDL) cholesterol (LDL-C) and premature coronary heart disease. Most of FH patients (about 95% of cases) are attributed to functional loss mutation of the LDL receptor (LDLR) gene. The prevalence of the heterozygous mutations in LDLR has been estimated at 1 in 200 to 1 in 500 in the population, and the homozygous form in 1 in 100000 individuals. As a key lipoprotein receptor on the surface of hepatocyte, the LDLR is critical for liver clearing LDL-C from the circulation. By endocytosis and further processing of the LDL-C, LDLR is responsible for removing most excess LDL-C from the serum, and there are no substitutes in vivo. These heterozygotes (HeFH) typically have twice the normal plasma LDL levels and cardiovascular diseases at an earlier age. Homozygous individuals (HoFH) face much higher LDL-C levels and often die before the age of 20 years if untreated. Although existing therapeutics, such as statins, ezetimibe and PCSK9 inhibitors, have some beneficial effects on HeFH, few drugs have therapeutic effects on HoFH even at high-doses. Lipid apheresis and liver transplantation are the current clinical managements to reduce the LDL-C level, while gene therapy holds the promise.
Exosomes are small intracellular vesicles ranging in 30-150 nm size and have an important role in cell-cell communication. Many studies show that exosome can efficiently deliver cargos, such as mRNA, miRNA and even plasmid DNA, to target cells, emerging as a promising therapeutic carrier for gene therapy. Compared with virus, exosomes, as "natural nanoparticles", are easy to handle, non-cytotoxic and non-immunogenic. It is thus promising to develop exosome-based LDLR-gene delivery strategy and explore the therapeutic effects on HoFH.
In this study, an Ldlr-expressing virus vector will be constructed to generate Ldlr mRNA-enriched exosomes. To meet the standards of clinical trials, we will use the GMP-grade compliant normal donor bone marrow-derived MSCs to produce exosomes. Exosomes will be enriched by filtration and ultracentrifugation, and then normalized by Nanosight, Electron microscopy and key exosomes biomarkers. In order to ensure the safety of patients, we plan to inject exosomes through abdominal puncture under ultrasound guidance, and purchase medical insurance for patients. This first-in-human study is aimed to evaluate the safety of this exosome product for gene therapy and preliminary evidence of efficacy using plasma LDL-C levels as a surrogate biomarker. The study is promising to provide a new therapeutic approach for the treatment of Homozygous Familial Hypercholesterolemia patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Homozygous Familial Hypercholesterolemia | Experimental | Biological: Low Density Lipoprotein Receptor mRNA Exosomes |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (12 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Low Density Lipoprotein Receptor mRNA ExosomesThe 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. | Biological | Homozygous Familial Hypercholesterolemia |
Primary outcome
Changes of Total Cholesterol
Time frame: Changes from Baseline Total Cholesterol at Day 19
mmol/L
Changes of Low-Density Lipoprotein Cholesterol
Time frame: Changes from Baseline Low-Density Lipoprotein Cholesterol at Day 19
mmol/L
Changes of High-Density Lipoprotein Cholesterol
Time frame: Changes from Baseline High-Density Lipoprotein Cholesterol at Day 19
mmol/L
Changes of Triglyceride
Time frame: Changes from Baseline Triglyceride at Day 19
mmol/L
3 secondary outcomes
Changes of Degree of Coronary Stenosis
Time frame: Changes from Baseline Degree of Coronary Stenosis at Day 28
Changes of Volume of Carotid Artery Plaques
Time frame: Changes from Baseline Volume of Carotid Artery Plaques at Day 28
Changes of Stability of Carotid Artery Plaques
Time frame: Changes from Baseline Stability of Carotid Artery Plaques at Day 28
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Sep 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Lijun Yuan principal investigator
The Second Affiliated Hospital of Air Force Military Medical University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Low Density Lipoprotein Receptor mRNA Exosomes in people with Familial Hypercholesterolemia, run by Tang-Du Hospital at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 14 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Zhelong Li (13319189556, lzlfmmu@foxmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes of Total Cholesterol (time frame: Changes from Baseline Total Cholesterol at Day 19). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Sep 2021.