To find out more about the podcast go to Audio long read: Faulty mitochondria cause deadly diseases — fixing them is about to get a lot easier.
Below is a short summary and detailed review of this podcast written by FutureFactual:
Editing Mitochondrial DNA: Base Editors Bring Hope for Mitochondrial Diseases
Nature’s long read explores how researchers are overcoming CRISPR’s limitations to edit mitochondrial DNA. By developing base editors that operate without guide RNA, scientists can modify MT DNA inside mitochondria, reduce faulty copies, and move toward treating diseases like LHON and MAS. Early lab successes in altering C to T and A to G in MT DNA have produced new animal models and important insights, while delivery, safety, and heteroplasmy remain key hurdles. The field is advancing toward preclinical studies and potential clinical trials within a decade, supported by biotech startups and academic collaborations.
Overview and Mitochondrial Genetics
CRISPR-Cas9 revolutionized gene editing in the nucleus, but MT DNA has remained largely inaccessible due to the mitochondrial membrane and the lack of RNA uptake. Mitochondrial DNA is maternally inherited, exists in multiple copies per cell, and mutations can cause serious diseases such as LHON and MAS syndrome. Heteroplasmy, the coexistence of healthy and mutated MT DNA copies, determines disease severity. Traditional nucleases could selectively reduce mutant copies, but they could not correct a wide range of mutations or provide durable fixes in patients.
Base Editing Breakthroughs
The turning point came with non-RNA–dependent editors. In 2018, David Lou and colleagues split a bacterial enzyme DDDA into two inactive pieces, directing it to MT DNA with engineered TALENs to create a base editor capable of C to T changes in MT DNA. Beverly Mock recalls the moment as a breakthrough: "The adrenaline rush that came with accomplishing such a technical feat is still vivid" - Beverly Mock. In 2022, Jinsuo Kim and colleagues added an A to G capability, expanding the mutation types that can be corrected. These tools rely on protein-based targeting rather than guide RNA, crossing the mitochondrial membranes to reach MT DNA.
From Lab Models to Disease Understanding
Base editors have already generated mouse and rat models of MT disease, including LHON and Li disease, enabling researchers to study how MT DNA is expressed and how editing affects cellular energy. Morais notes a fundamental challenge: "Nobody understands this process well" - Morais. Yet edited MT DNA can restore healthy DNA proportions in animal tissues, providing valuable models for studying pathophysiology and screening potential therapies.
Clinical Translation and Remaining Hurdles
Moving MT DNA editing toward the clinic faces hurdles similar to those for nuclear CRISPR: safety, specificity, and effective delivery to target organs such as brain, heart, and muscle. Foos emphasizes the challenge of translation: "Moving MT DNA editing into the clinic faces many of the same hurdles that hinder CRISPR editing," - Foos. Nonetheless, industry players like Premera Therapeutics and Precision Biosciences are pursuing base editors and heteroplasmy modulation as potential routes to therapies. Mougeau and Kim believe the foundational science is maturing, with ongoing work to broaden the range of mutations addressable by MT editors. Kim calls the development a potential "medical breakthrough", while Mougeau remains hopeful that new editors will extend reach and safety.
Outlook and Impact
Despite the decade-long horizon to clinic, these tools already offer valuable disease models and mechanisms to study mitochondrial biology, including codependent RNA expression from MT DNA. The field is poised to deliver targeted therapies that do not require altering the nuclear genome, offering new options for patients with LHON, MAS syndrome, and related conditions. As editors broaden their mutation coverage and delivery strategies improves, MT DNA therapies could transform treatment paradigms for mitochondrial diseases before a full clinical roll-out, with many detailed studies guiding regulatory and safety frameworks.
It would be a medical breakthrough - Kim