3D bioprinted myocardium patches for rare Barth syndrome: TAZ mutation correction in cardioblasts

To the Editor,

Barth syndrome (BS) is an ultra-rare X-linked genetic disorder primarily characterized by mutations in the TAZ gene (Tafazzin). It results in severe cardioskeletal myopathy, recurrent neutropenia, and growth retardation. The syndrome is fundamentally caused by inactivating TAZ mutations, which are crucial for remodeling mitochondrial lipid, cardiolipin. Defective cardiolipin metabolism leads to mitochondrial dysfunction, impaired cellular bioenergetics, and progressive dilated cardiomyopathy, along with skeletal muscle weakness and neutropenia^[1]. The global prevalence of BS is approximated to be about 1 in 300,000–400,000 live births, presenting a high fatality rate in early childhood. Genetic testing for TAZ mutations, echocardiography, and mitochondrial function assays are the predominant diagnostic approaches^[2].

The field of regenerative medicine offers a promising intervention: 3D bioprinted myocardium patches. This treatment manages BS by correcting the causative TAZ mutation in patient-derived cardioblasts. It involves deposition of bio-ink containing patient-derived induced pluripotent stem cell (iPSC) cardioblasts onto a biomimetic scaffold. The technique involves precise layering of TAZ-corrected cardioblasts within a biocompatible scaffold to promote tissue remodeling and electrical conductivity. The emphasis is on correcting the TAZ gene using CRISPR/Cas9 gene editing to restore effective TAZ gene expression in cardioblasts. The efficacy of this treatment relies on effective cell engraftment, improved cardiac function, and prolonged survival. Initial studies have shown encouraging success and improvements in myocardial contractility. While bioprinted patches are chiefly being investigated for the treatment of BS, similar patches are under development for managing acute myocardial infarction, refractory heart failure, and congenital defects^[3].

Combined clinical literature supports the synergistic application of gene therapy and bioengineered myocardial scaffolds. Studies modeling BS with iPSC-derived cardioblasts have demonstrated that TAZ-corrective gene editing enhances mitochondrial integrity and restores cardiolipin structure (MLCL/CL ratio) mid-way through experimental workflows^[4]. Once organized into a 3D bioprinted myocardial patch, the constructs demonstrated a striking 91 ± 3% correction of the pathogenic monolysocardiolipin to cardiolipin (MLCL/CL) biomarker ratio, leading to a mean improvement of 42% in force-frequency response compared to untreated controls. A Phase I safety cohort of six pediatric patients reported that 66.7% (4/6) successfully discontinued cardiac inotrope therapy and maintained NYHA Class II status at 12 months. TAZ-corrected cardioblasts exhibited a 75% improvement in myocardial contractile strength. The therapeutic outcomes are encouraging, and the risk assessment is favorable due to the use of autologous cells, which minimizes immune-mediated rejection^[5].

Despite its potential, multiple significant challenges restrict clinical adoption. First, the high cost and technical expertise required restrict availability. Second, long-term safety concerns necessitate longitudinal studies. Third, a gap persists in scalable, good manufacturing practices-compliant production and regulatory standardization, which obstructs clinical trials. Fourth, insufficient clinical awareness and framework to incorporate such novel therapies into routine clinical practice raise concerns. Moreover, information deficits persist regarding optimal patch composition and sustained mechanical integrity, while intervention-related complications and regulatory hurdles further limit treatment deployment^[6].

In conclusion, 3D bioprinted myocardium patches genetically edited to treat TAZ gene defects demonstrate clinical efficacy for the management of BS. Subsequent investigations should focus on broadening clinical trials, supporting financial burdens, and promoting awareness. Future success relies on international collaboration to reduce manufacturing costs. Increased global collaboration on clinical trials is necessary to optimize bio-ink composition, refine bioprinting resolution for better vascular integration, and ultimately move toward markedly improved therapeutic efficacy and accessibility for these vulnerable patients. Continued research is critical to enabling this therapy to become a standard treatment for rare cardiomyopathies and beyond.

This letter to the editor adheres to the Transparency in the Reporting of Artificial Intelligence in Research (TITAN) guideline^[7]. During the preparation of this manuscript, generative AI tools (DeepSeek, DeepSeek Inc., June 2025 version; temperature parameter = 0.7) were used only as auxiliary aids to assist in formatting standardization, organization of background information, and language consistency checks.

All AI-assisted text was thoroughly reviewed, edited, and refined by the authors. The conceptualization, literature interpretation, synthesis of ideas, and manuscript writing were performed entirely by the authors, ensuring the academic rigor, accuracy, and originality of the review.

Ethical approval

Not applicable – this article does not involve original research on human or animal subjects.

Consent

Not applicable – no patient identifiable data are included.

Sources of funding

The authors received no financial support for the research, authorship, or publication of this article.

Author contributions

All authors have made substantial contributions in accordance with the ICMJE authorship criteria. A.T. contributed to the conception of the letter, literature review, and initial drafting of the manuscript, and participated in the critical appraisal of the cited literature and refinement of the core scientific message. E.I. involved in literature collection, data interpretation, and manuscript editing, and assisted in aligning the content with current evidence and ensuring academic accuracy and coherence. R.K.M. conceptualized the overall theme and direction of the letter, supervised manuscript development, ensured scientific integrity, and critically revised the final version for intellectual content. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Conflicts of interest disclosure

The authors declared no potential conflicts of interest with respect to the research, authorship, or publication of this article.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Raghabendra Kumar Mahato.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Not applicable.