TN-201 for Hypertrophic Cardiomyopathy (MyPEAK-1 Trial)
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Tenaya Therapeutics
No Placebo Group
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?This trial tests a new drug, TN-201, in adults with a specific genetic heart condition. It aims to see if the drug is safe and how it affects their health over several years.
Is TN-201 a promising treatment for Hypertrophic Cardiomyopathy?Yes, TN-201 is a promising treatment for Hypertrophic Cardiomyopathy because it uses a special delivery system that targets heart cells specifically, improving the effectiveness of the treatment. This approach helps ensure that the treatment works well in the heart while reducing effects on other parts of the body.12678
What safety data exists for TN-201 treatment for Hypertrophic Cardiomyopathy?The safety data for TN-201, which involves the use of AAV9 capsid with a cardiomyocyte-specific promoter and the MYBPC3 gene, includes several studies. One study in swine showed successful targeted delivery of cardiomyocyte-selective AAV9 vectors without negative side effects, indicating no toxic effects on cardiac and systemic markers. Another study in mice demonstrated that AAV9-Mybpc3 gene therapy prevented cardiac hypertrophy and dysfunction without adverse effects over a 34-week observation period. These findings suggest that the treatment is safe in preclinical models, but further studies are needed to confirm safety in humans.23467
What data supports the idea that TN-201 for Hypertrophic Cardiomyopathy is an effective treatment?The available research shows that TN-201, which involves gene therapy using the Mybpc3 gene, has been effective in preventing heart problems in mice with a condition similar to Hypertrophic Cardiomyopathy. In one study, a single treatment given to newborn mice stopped the development of heart enlargement and dysfunction for 34 weeks. This suggests that TN-201 could be a promising long-term treatment option for this heart condition, especially since there are few other treatments available besides heart transplants.23457
Do I have to stop taking my current medications for the trial?The trial protocol does not specify whether you need to stop taking your current medications.
Eligibility Criteria
This trial is for adults with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) linked to MYBPC3 mutation. Participants must have certain heart function markers like NT-proBNP levels of at least 300pg/ml and a left ventricular ejection fraction of 50% or more, as well as an implantable cardiac defibrillator.Inclusion Criteria
I have a thickened heart muscle that isn't blocking blood flow.
I have a MYBPC3 gene mutation.
I have moderate to moderately severe heart symptoms.
I have a working heart defibrillator and moderate heart symptoms.
Treatment Details
The study is testing TN-201, a new treatment for nHCM. It's the first time this drug is being given to humans. The trial will look at how safe it is, how well people can tolerate it, and what effects it has on the body.
2Treatment groups
Experimental Treatment
Group I: Cohort 2Experimental Treatment1 Intervention
Dose for Cohort 2 will be 6E13 vg/kg
Group II: Cohort 1Experimental Treatment1 Intervention
Dose for Cohort 1 will be 3E13 vg/kg
TN-201 is already approved in United States, European Union for the following indications:
๐บ๐ธ Approved in United States as TN-201 for:
- None approved yet; under investigation for MYBPC3-associated hypertrophic cardiomyopathy (HCM)
๐ช๐บ Approved in European Union as TN-201 for:
- None approved yet; under investigation for MYBPC3-associated hypertrophic cardiomyopathy (HCM)
Find a clinic near you
Research locations nearbySelect from list below to view details:
University of Texas Southwestern Medical CenterDallas, TX
The Christ Hospital Physicians - The Ohio Heart and Vascular CenterCincinnati, OH
Brigham and Women's HospitalBoston, MA
Oregon Health & Science UniversityPortland, OR
More Trial Locations
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Who is running the clinical trial?
Tenaya TherapeuticsLead Sponsor
References
Heart muscle-specific gene expression using replication defective recombinant adenovirus. [2006]Adenoviruses are a promising vector system for future gene therapy of heart muscle diseases. The promiscuous tissue tropism of adenoviruses, however, may lead to the undesirable expression of putative therapeutic genes in nontarget cells and hence to considerable safety limitations for this vector system. To restrict gene expression to cardiomyocytes we constructed an adenoviral vector (Ad-mlcLuc) in which the luciferase gene is under the control of the ventricle-specific myosin light chain-2 (mlc-2v) promoter. For controls, we constructed a recombinant adenovirus without promoter (Ad-Luc) and one with the Rous sarcoma virus (RSV) promoter (Ad-rsvLuc). Our data demonstrate that the newly established viral vector Ad-mlcLuc was specifically active in rat neonatal cardiomyocytes in vitro but not in three established cell lines. Injections of the recombinant adenoviruses into the cardiac cavity of neonatal rats resulted in myocardial specific gene expression of Ad-mlcLuc in vivo, despite the fact that viral DNA was detected by PCR at different levels in all tissues investigated. In vitro and in vivo, Ad-mlcLuc was exclusively active in cardiac muscle cells, reaching 8-9% of the RSV-induced luciferase activity. Direct injection of Ad-mlcLuc into thigh muscle gave only background luciferase activity (0.05% of Ad-rsvLuc). Therefore, in the adenoviral system, the mlc-2v promoter allows heart-specific expression of a foreign gene thus providing a promising tool for gene transfer targeted to the myocardium.
Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice. [2020]The AAV9 capsid displays a high natural affinity for the heart following a single intravenous (IV) administration in both newborn and adult mice. It also results in substantial albeit relatively lower expression levels in many other tissues. To increase the overall safety of this gene delivery method we sought to identify which one of a group of promoters is able to confer the highest level of cardiac specific expression and concurrently, which is able to provide a broad biodistribution of expression across both cardiac and skeletal muscle. The in vivo behavior of five different promoters was compared: CMV, desmin (Des), alpha-myosin heavy chain (alpha-MHC), myosin light chain 2 (MLC-2) and cardiac troponin C (cTnC). Following IV administration to newborn mice, LacZ expression was measured by enzyme activity assays. Results showed that rAAV2/9-mediated gene delivery using the alpha-MHC promoter is effective for focal transgene expression in the heart and the Des promoter is highly suitable for achieving gene expression in cardiac and skeletal muscle following systemic vector administration. Importantly, these promoters provide an added layer of control over transgene activity following systemic gene delivery.
Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. [2021]Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM.
Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice. [2014]Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.
Targeting mAKAPฮฒ expression as a therapeutic approach for ischemic cardiomyopathy. [2023]Ischemic cardiomyopathy is a leading cause of death and an unmet clinical need. Adeno-associated virus (AAV) gene-based therapies hold great promise for treating and preventing heart failure. Previously we showed that muscle A-kinase Anchoring Protein ฮฒ (mAKAPฮฒ, AKAP6ฮฒ), a scaffold protein that organizes perinuclear signalosomes in the cardiomyocyte, is a critical regulator of pathological cardiac hypertrophy. Here, we show that inhibition of mAKAPฮฒ expression in stressed adult cardiomyocytes in vitro was cardioprotective, while conditional cardiomyocyte-specific mAKAP gene deletion in mice prevented pathological cardiac remodeling due to myocardial infarction. We developed a new self-complementary serotype 9 AAV gene therapy vector expressing a short hairpin RNA for mAKAPฮฒ under the control of a cardiomyocyte-specific promoter (AAV9sc.shmAKAP). This vector efficiently downregulated mAKAPฮฒ expression in the mouse heart in vivo. Expression of the shRNA also inhibited mAKAPฮฒ expression in human induced cardiomyocytes in vitro. Following myocardial infarction, systemic administration of AAV9sc.shmAKAP prevented the development of pathological cardiac remodeling and heart failure, providing long-term restoration of left ventricular ejection fraction. Our findings provide proof-of-concept for mAKAPฮฒ as a therapeutic target for ischemic cardiomyopathy and support the development of a translational pipeline for AAV9sc.shmAKAP for the treatment of heart failure.
Distribution of cardiomyocyte-selective adeno-associated virus serotype 9 vectors in swine following intracoronary and intravenous infusion. [2023]Limited reports exist regarding adeno-associated virus (AAV) biodistribution in swine. This study assessed biodistribution following antegrade intracoronary and intravenous delivery of two self-complementary serotype 9 AAV (AAV9sc) biologics designed to target signaling in the cardiomyocyte considered important for the development of heart failure. Under the control of a cardiomyocyte-specific promoter, AAV9sc.shmAKAP and AAV9sc.RBD express a small hairpin RNA for the perinuclear scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) and an anchoring disruptor peptide for p90 ribosomal S6 kinase type 3 (RSK3), respectively. Quantitative PCR was used to assess viral genome (vg) delivery and transcript expression in Ossabaw and Yorkshire swine tissues. Myocardial viral delivery was 2-5 × 105 vg/µg genomic DNA (gDNA) for both infusion techniques at a dose ∼1013 vg/kg body wt, demonstrating delivery of ∼1-3 viral particles per cardiac diploid genome. Myocardial RNA levels for each expressed transgene were generally proportional to dose and genomic delivery, and comparable with levels for moderately expressed endogenous genes. Despite significant AAV9sc delivery to other tissues, including the liver, neither biologic induced toxic effects as assessed using functional, structural, and circulating cardiac and systemic markers. These results indicate successful targeted delivery of cardiomyocyte-selective viral vectors in swine without negative side effects, an important step in establishing efficacy in a preclinical experimental setting.
AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes. [2023]AAV vectors are promising delivery tools for human gene therapy. However, broad tissue tropism and pre-existing immunity against natural serotypes limit their clinical use. We identified two AAV capsid variants, AAV2-THGTPAD and AAV2-NLPGSGD, by in vivo AAV2 peptide display library screening in a murine model of pressure overload-induced cardiac hypertrophy. Both variants showed significantly improved efficacy in in vivo cardiomyocyte transduction compared with the parental serotype AAV2 as indicated by a higher number of AAV vector episomes in the nucleus and significant improved transduction efficiency. Both variants also outcompeted the reference serotype AAV9 regarding cardiomyocyte tropism, reaching comparable cardiac transduction efficiencies accompanied with liver de-targeting and decreased transduction efficiency of non-cardiac cells. Capsid modification influenced immunogenicity as sera of mice treated with AAV2-THGTPAD and AAV2-NLPGSGD demonstrated a poor neutralization capacity for the parental serotype and the novel variants. In a therapeutic setting, using the long non-coding RNA H19 in low vector dose conditions, novel AAV variants mediated superior anti-hypertrophic effects and revealed a further improved target-to-noise ratio, i.e., cardiomyocyte tropism. In conclusion, AAV2-THGTPAD and AAV2-NLPGSGD are promising novel tools for cardiac-directed gene therapy outperforming AAV9 regarding the specificity and therapeutic efficiency of in vivo cardiomyocyte transduction.
Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. [2022]Bioengineering of viral vectors for therapeutic gene delivery is a pivotal strategy to reduce doses, facilitate manufacturing, and improve efficacy and patient safety. Here, we engineered myotropic adeno-associated viral (AAV) vectors via a semirational, combinatorial approach that merges AAV capsid and peptide library screens. We first identified shuffled AAVs with increased specificity in the murine skeletal muscle, diaphragm, and heart, concurrent with liver detargeting. Next, we boosted muscle specificity by displaying a myotropic peptide on the capsid surface. In a mouse model of X-linked myotubular myopathy, the best vectors-AAVMYO2 and AAVMYO3-prolonged survival, corrected growth, restored strength, and ameliorated muscle fiber size and centronucleation. In a mouse model of Duchenne muscular dystrophy, our lead capsid induced robust microdystrophin expression and improved muscle function. Our pipeline is compatible with complementary AAV genome bioengineering strategies, as demonstrated here with two promoters, and could benefit many clinical applications beyond muscle gene therapy.