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Mitochondrial diseases affect approximately 1 in 5,000 people worldwide, causing debilitating symptoms ranging from muscle weakness to stroke-like episodes. These conditions result from mutations in mitochondrial DNA (mtDNA), which is housed in the mitochondria, the powerhouses of cells. For patients with the common m.3243A>G mutation, treatments remain limited. A fundamental challenge in mitochondrial disease research is that patients typically have a mix of both normal and mutated mtDNA within their cells, known as heteroplasmy.

This condition makes targeted therapies difficult to develop, as the normal-to-mutated mtDNA ratios can vary greatly from tissue to tissue. Current basic research into mtDNA mutations faces significant obstacles due to a lack of disease models. The complex relationship between mutation load and disease severity remains poorly understood because there are no tools to precisely manipulate heteroplasmy levels in either direction.

Against this backdrop, a research team led by Senior Assistant Professor Naoki Yahata from the Department of Developmental Biology, Fujita Health University School of Medicine, Japan, has developed a technology that can modify heteroplasmy levels in cultured cells carrying the m.3243A>G mutation. Their paper was made available online on March 20, 2025, and will be published in Volume 36, Issue 2 of the journal Molecular Therapy Nucleic Acids on June 10, 2025.

The researchers established cultures of patient-derived induced pluripotent stem cells (iPSCs) containing the m.3243A>G mutation and designed two versions of their mtDNA-targeted platinum transcription activator-like effector nucleases (mpTALENs). One version targets mutant mtDNA for destruction, while the other targets normal mtDNA. This bi-directional approach allowed them to generate cells with mutation loads ranging from as low as 11% to as high as 97%, while still maintaining the cells’ ability to differentiate into various tissue types.

The researchers also employed additional techniques, such as uridine supplementation, to establish stable cell lines with different mutation loads. Their results demonstrate that their mpTALEN optimization process created a useful tool for altering heteroplasmy levels in m.3243A>G-iPSCs, improving their potential for studying mutation pathology.

Overall, the study represents a significant advancement in mitochondrial medicine for several reasons. It provides researchers with multiple isogenic cell lines that differ only in their level of heteroplasmy, allowing for a precise study of how mutation load affects disease manifestation. The mpTALEN technology may become therapeutically valuable for reducing mutant mtDNA load in patients.

The proposed method could be adapted for other mutant mtDNAs and may contribute to understanding their associated pathologies and developing new treatments, potentially benefiting patients with various forms of mitochondrial disease.

The most critical complication to watch out for after receiving a lung transplant is Chronic Lung Allograft Dysfunction (CLAD). Once CLAD develops, there are no universally effective treatments available. Therefore, preventing this complication takes top priority for those who have undergone a lung transplant. One of the primary immunosuppressing medications used in lung transplant recipients is calcineurin inhibitors.

There are only two calcineurin inhibitors: cyclosporine and tacrolimus. Each has different formulations, such as once-daily slow-release tacrolimus, twice-daily immediate-release tacrolimus, and twice-daily cyclosporine. While these medications share the same goal of preventing rejection, it is unclear whether they are equally effective. CLAD encompasses a range of clinical manifestations that ultimately lead to the transplanted lung losing its normal function.

The presentation of CLAD can vary among patients, with some experiencing an obstructive ventilatory defect, others having a restrictive defect, and some exhibiting a combination of both. Unfortunately, once CLAD develops, lung function does not improve. In the absence of effective treatments, strategies to prevent CLAD are crucial.

A recent study published in the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry data found a significant survival benefit between using tacrolimus versus cyclosporine after lung transplantation. Out of 22,222 individuals with data on chronic lung allograft dysfunction treatment, 88.6% received immediate-release tacrolimus. The participants taking immediate-release tacrolimus had a much lower rate of experiencing CLAD than those who took twice-daily cyclosporine.

Michael Combs, an assistant professor of pulmonary diseases and internal medicine at Michigan Medicine, led the research team conducting this study. Combs highlighted the positive findings for twice-daily immediate-release tacrolimus in this study, stating that it should reassure transplant patients and providers that using this formulation is the superior treatment to cyclosporine.

“This present study should reassure transplant patients and providers twice-daily tacrolimus — and not only once-daily tacrolimus — is the superior treatment to cyclosporine,” said Combs. “Importantly, in our study we found that twice-daily tacrolimus not only resulted in lower rates of CLAD relative to cyclosporine, but it was also associated with improved overall survival after lung transplantation. This is an important, patient-centered finding which has not been previously demonstrated.”

In conclusion, the most effective prevention method for complications post-lung transplant is using tacrolimus, regardless of its formulation. This treatment offers a significant advantage over cyclosporine in preventing CLAD and improving overall survival after lung transplantation. Future research will need to investigate whether once-daily medication regimens are superior to twice-daily formulations.

Researchers at the University of California, Los Angeles (UCLA) have made a groundbreaking discovery that could revolutionize the treatment of chronic kidney disease (CKD). A study published in Science Translational Medicine has uncovered a critical factor that determines how much scarring occurs following kidney injury, leading scientists to identify a potential precision medicine approach to prevent CKD progression.

The researchers, led by Dr. Arjun Deb, found that type 5 collagen – a minor component of scar tissue – plays a crucial role in maintaining the structure and function of scar tissue. They discovered that differences in type 5 collagen expression help explain why some people develop more extensive kidney scarring than others.

This breakthrough has significant implications for the treatment of CKD, which affects over 800 million people worldwide. Currently, there are no therapies that directly target or reverse fibrosis, a process that impairs the kidneys’ ability to filter toxins from the blood and reabsorb water, often leading to kidney failure.

The study involved analyzing data from the UK Biobank, a long-term study tracking more than 1.5 million people. The researchers found that expression of Col5a1, the gene encoding type 5 collagen, strongly correlated with the risk of developing CKD over the course of a decade.

A series of experiments in mouse models confirmed these findings: Mice with low Col5a1 developed more severe fibrosis and progressed more rapidly to kidney failure following kidney injury. As with humans, type 5 collagen was playing a crucial role in maintaining the structure and function of scar tissue.

The researchers identified a potential solution in Cilengitide, a drug that disrupts integrin signaling. They found that treating animals with decreased type 5 collagen with Cilengitide significantly reduced kidney fibrosis and slowed disease progression. Notably, it had no effect in mice with normal Col5a1 expression, highlighting its potential as a targeted therapy for individuals at risk of rapid disease progression.

This presents an exciting opportunity to potentially repurpose this drug, which was already deemed safe by the FDA, for a completely different indication.

The researchers are now working to establish a blood test to measure Col5a1 levels in human patients with CKD to establish a clinical threshold for identifying at-risk individuals. If validated, this biomarker could be used to guide treatment decisions, pinpointing patients who could benefit from this targeted approach to slowing disease progression.

Beyond CKD, the researchers are also investigating whether the same mechanisms contribute to fibrosis in the liver and blood vessels, where scarring is a major driver of disease.

The use of Cilengitide has not been tested in humans as a treatment for excessive scarring and has not been approved by the Food and Drug Administration as safe and effective for this use. This novel therapeutic approach is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California.

The study’s findings have significant implications for the treatment of CKD, and further research is needed to validate these results and explore their potential applications in humans.