Myocardial Telomere Recapping Study for Dilated Cardiomyopathy

NCT05837143 | Active Not Recruiting Early Phase 1

• 1 other identifier: JV001-02
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this study is to determine the safety and feasibility of giving an adeno-associated viral vector expressing a modified telomerase protein (TERT), driven by cardiac troponin T promoter (AAV9-cTnT-modTERT), to 12 dilated cardiomyopathic patients.

Conditions

Heart Failure; Dilated Cardiomyopathy

Keywords

Adeno-associated virus; modTERT; Dilated Cardiomyopathy

Outcome Measures

Primary Outcomes (2)

• Dose-limiting toxicity (DLT) within 28 days of a single intracoronary infusion of JV001

  To evaluate the DLT occurred within 28 days after JV001 infusion

  28 days

• Incidence of adverse events and serious adverse events within 1 year of administration

  To evaluate the safety of JV001 treatment

  1 year

Secondary Outcomes (8)

• Left ventricular ejection fraction

  Baseline, Week 12, Week 26, Week 52

• Myocardial remodeling assessed by Cardiac Magnetic Resonance (CMR) Imaging

  Baseline, Week 26

• Change in N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) from baseline to Week 2, 4, 12, 26, 52

  Baseline, Week 2, Week 4, Week 12, Week 26, Week 52

• Change in 6-minute Walk Test (6MWT) from baseline to Week 12，26，52

  Baseline, Week 12, Week 26, Week 52

• Change in total immunoglobulin and neutralizing antibodies from baseline to Week 2, Week 4, Week 12, Week 26, Week 52

  Baseline, Week 2, Week 4, Week 12, Week 26, Week 52

Other Outcomes (19)

• Change in standard uptake value (SUV) of 18F-fluorodeoxyglucose-positron emission tomography (PET) imaging from baseline to Week 26.

  Baseline, Week 26

• Late gadolinium enhancement (LGE) by Cardiac Magnetic Resonance (CMR) Imaging

  Baseline, Week 26

• Biomarkers for Heart Failure and Prognosis

  Baseline, Week 2, Week 4, Week 12, Week 26, Week 52

Study Arms (1)

Active Comparator: JV001

EXPERIMENTAL

Subjects will receive a single intracoronary infusion of JV001 at a dose of 2×10\^11vg/kg, and 6×10\^11vg/kg.

Biological: JV001

Interventions

JV001 BIOLOGICAL

JV001 (AAV9/modTERT) will be delivered by a percutaneous method in the catheter laboratory. Dose: 2×10\^11vg/kg，or 6×10\^11vg/kg.

Active Comparator: JV001

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• DCM≥1year;
• NYHA II-IV;
• LVEF ≤35%；
• Received maximally tolerated guideline-directed medical therapy (GDMT) for at least 3 months before enrollment with persistent heart failure; or unable to tolerate standardized pharmacotherapy recommended by guidelines (according to clinical data), but in which investigators assessed participants who could benefit from the study drug; or hospitalized for heart failure more than 2 times within 1 year and requiring intravenous diuretic therapy, while the condition is stable for more than 2 weeks;
• Have the ability to understand and voluntarily sign informed consent before the trial, and be able to complete the study in accordance with the requirements of the trial protocol;
• Male or female: (1) male subjects must agree to use contraception for at least 6 months after treatment visit; (2) the female subjects were not pregnant or breastfeeding; (3) Females of childbearing potential agree to comply with contraceptive guidance for at least 6 months after administration (see Appendix 1)

You may not qualify if:

• Patients with heart failure caused by heart diseases other than dilated cardiomyopathy (including but not limited to severe valvular heart disease, hyperthyroidism, congenital heart disease, acute viral myocarditis, acute coronary syndrome, hypertrophic obstructive cardiomyopathy, pericardial disease, myocardial amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease, or left ventricular aneurysm).
• Coronary angiography has a degree of narrowing of the left main coronary artery (LM), left anterior descending branch (LAD), left circumflex branch (LCX) or right coronary artery (RCA) \> 50%.
• Uncontrolled arrhythmias that the investigator believes would affect this trial.
• Acute myocardial infarction within 6 months before screening
• Previous presence of subjects with immunological abnormalities that the investigators believe could affect this trial (including but not limited to congenital immunodeficiency, lupus erythematosus, primary vasculitis, systemic sclerosis, antiphospholipid syndrome, autoimmune liver disease, autoimmune thyroiditis).
• Those who have a history of tumor for less than 5 years or currently have a tumor, or those who have precancerous lesions confirmed by pathological examination (including but not limited to breast ductal carcinoma in situ, cervical dysplasia, etc.)
• Known progress liver disease (active hepatitis A, chronic hepatitis B or C virus infection, non-cardiogenic cirrhosis, etc.)
• Acute infection developed within 2 weeks prior to screening requiring intravenous antibiotic therapy, or current infection requiring anti-infective therapy.
• Those who have a history of disseminated herpes simplex infection or recurrent (\> 1 times) or disseminated herpes zoster.
• Percutaneous coronary intervention (PCI), coronary bypass grafting (CABG), Implantable Cardioverter Defibrillator (ICD)/permanent pacemaker/Cardiac resynchronisation therapy (CRT) implantation, radiofrequency ablation, ventricular volume reduction, valve repair or plasty, intra-aortic balloon counterpulsation, passive restraint devices (e.g., CorCap™ cardiac support devices), cardiac assist device implantation, heart transplantation, or other cardiac surgery may be received within 3 months prior to screening or within 3 months after administration.
• Those who donated ≥ 400 mL of blood within 4 weeks prior to screening, or who had significant blood loss equivalent to at least 400 mL, or who received blood transfusions within 8 weeks.
• Subjects with contraindications for coronary angiography
• Contraindications for Magnetic Resonance Imaging (MRI) detection, including but not limited to: pacemaker, defibrillator, artificial heart valve, metal clip after aneurysm surgery, drug perfusion device implanted in the body, any electronic device implanted in the body (neurostimulator, bone growth stimulator), intravascular embolization steel ring, filter, ECG recording monitor, shrapnel or iron sand in the body, fixed steel plate and nails after fracture surgery, cochlear implant, intraocular metal foreign body, etc.; Claustrophobia, etc.
• Those who have a history of substance abuse within the past five years or have used drugs in the 3 months prior to the test.
• Are participating in other clinical trials, or have been completed less than 3 months after the end of other clinical trials.

Sponsors & Collaborators

• Shanghai East Hospital: lead
• Shanghai Juvensis Therapeutics Biotechnology Company Limited: collaborator

Study Sites (1)

Shanghai East Hospital

Shanghai, Shanghai Municipality, 200120, China

Location

Related Publications (4)

• Schultheiss HP, Fairweather D, Caforio ALP, Escher F, Hershberger RE, Lipshultz SE, Liu PP, Matsumori A, Mazzanti A, McMurray J, Priori SG. Dilated cardiomyopathy. Nat Rev Dis Primers. 2019 May 9;5(1):32. doi: 10.1038/s41572-019-0084-1.

  PMID: 31073128 BACKGROUND

• Chang ACY, Chang ACH, Kirillova A, Sasagawa K, Su W, Weber G, Lin J, Termglinchan V, Karakikes I, Seeger T, Dainis AM, Hinson JT, Seidman J, Seidman CE, Day JW, Ashley E, Wu JC, Blau HM. Telomere shortening is a hallmark of genetic cardiomyopathies. Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9276-9281. doi: 10.1073/pnas.1714538115. Epub 2018 Aug 27.

  PMID: 30150400 BACKGROUND

• Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, Maser RS, Tonon G, Foerster F, Xiong R, Wang YA, Shukla SA, Jaskelioff M, Martin ES, Heffernan TP, Protopopov A, Ivanova E, Mahoney JE, Kost-Alimova M, Perry SR, Bronson R, Liao R, Mulligan R, Shirihai OS, Chin L, DePinho RA. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011 Feb 17;470(7334):359-65. doi: 10.1038/nature09787. Epub 2011 Feb 9.

  PMID: 21307849 BACKGROUND

• Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019 May;18(5):358-378. doi: 10.1038/s41573-019-0012-9.

  PMID: 30710128 BACKGROUND

MeSH Terms

Conditions

Heart Failure; Cardiomyopathy, Dilated

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Cardiomegaly; Cardiomyopathies; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Head of Heart Failure Unit, Principal Investigator, Clinical Professor

Study Record Dates

• First Submitted: March 24, 2023
• First Posted: May 1, 2023
• Study Start: March 30, 2023
• Primary Completion: July 30, 2025
• Study Completion: December 30, 2025
• Last Updated: July 16, 2024

Record last verified: 2024-07

Locations

CN (1)