Powering prescription: Mitochondria as "Living Drugs" - Definition, clinical applications, and industry advancements

Abstract

Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as "Living Drugs" (LDs). Artificial mitochondrial transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine.

Keywords: Acellular therapy; Advanced therapeutic medicinal products (ATMPs); Artificial mitochondrial transfer transplant (AMT/T); Cell therapy; Industry; Innovation; Living drugs (LDs); Mitochondria.

Fig. 1.

Living Drugs (LDs): harnessing cellular and subcellular entities for therapy. Representation of LDs as multifaceted biological entities, sourced from a variety of anatomical origins and depicted as both whole cells and subcellular components. LDs are amenable to ex vivo culture and precision genetic engineering, highlighting their capability for expansion and tailored therapeutic delivery. The intrinsic ability of LDs to undergo genetic modification is key to their function in protein synthesis and therapeutic action, offering both temporary and long-lasting effects personalized to patient-specific requirements. Upon administration, LDs demonstrate remarkable biological plasticity by proliferating, evolving, and interacting dynamically with the patient’s internal environment (extracellular and intracellular), showcasing their potential for sustained presence and therapeutic benefit. Created with biorender.com.

Fig. 2.

Mitochondria as Living Drugs: they can exhibit distinct genotypes and phenotypes that may induce therapeutic effects. From left to right: Distinct biological origins endow mitochondria with diversity, as they can be isolated from various cells, platelets, vesicles, and tissues [2,3,51,76,77]. They may retain unique characteristics from their source of origin that could influence their effects on recipient cells and tissues [51,78]. Mitochondria maintain their own mtDNA, which is susceptible to modifications or may carry unique mitochondrial gene sequences that can induce specific effects in cells [52,70,71]. Mitochondria can interact with the intracellular environment, leading to various outcomes such as enhanced mitochondrial biogenesis, increased oxidative phosphorylation capacity, and cell proliferation [36,49]. Mitochondria could be cultivated in large quantities using specialized bioreactors for cells, platelets, or other mediums conducive to mitochondrial growth, expansion, and survival. The therapeutic potential of mitochondria has been demonstrated following their transfer to cells and transplantation into tissues [57,79,80]. When mitochondria are exposed to different metabolic stimulants and then transferred or transplanted, they can induce a range of effects. For example, transferring both functional and depolarized mitochondria can differentially enhance the bioenergetics of the recipient cells [72]. Remarkably, it has been shown that transferring certain types of mitochondria can prompt cells to boost mitochondrial biogenesis and, in turn, facilitate the transfer of other types of mitochondria [81].