Among genetic diseases, primary mitochondrial disease is one of the most common, severe, and complex, with a birth prevalence of at least 1 in 5000. These diseases are multi-genic and multi-phenotypic, affecting all ages, from prenatal to adult. Protheragen provides comprehensive, end-to-end customized research and development services tailored to overcome the unique challenges in primary mitochondrial disease diagnostics and therapeutics, accelerating the path from discovery to application.
Overview of Primary Mitochondrial Diseases
Primary mitochondrial diseases are an assortment of genetic conditions marked by a defect of the mitochondrial respiratory chain. They are caused by pathogenic variants in nuclear DNA or mitochondrial DNA that compose the subunit structures or assembly factors of the respiratory chain. Because of this, these diseases manifest in an almost innumerable way, with symptoms ranging from severe multisystem disorders from infancy, to those of adult-onset myopathic or neurological disorders. Symptoms are most commonly associated with high-energy-demand organs, including the brain, skeletal, cardiac, and liver. The complexity of the condition and the absence of a clear genotype-phenotype relationship are what make primary mitochondrial diseases especially challenging in regard to diagnosis and the development of a drug.
Fig.1 Key mitochondrial diseases manifestations and red flags. (Conti, F., et al., 2023)
Biomarkers of Primary Mitochondrial Diseases
Lactate
Increased levels in blood or CSF frequently indicate compromised oxidative phosphorylation and resulting anaerobic metabolism.
Pyruvate
Often studied together with lactate, an elevated lactate-to-pyruvate ratio is highly indicative of a respiratory chain defect.
Creatine kinase
Increased in plasma, and is a marker of skeletal muscle damage or myopathy, often observed with mitochondrial disorders.
FGF-21
A growth factor that mediates lipid and glucose metabolism, associated with mitochondrial dysfunction.
GDF-15
Stress-responsive cytokine levels are significantly elevated, providing a highly sensitive biomarker for primary mitochondrial disorders.
Acylcarnitine
Plasma profiles reflect impaired fatty acid oxidation resulting from mitochondrial beta-oxidation defects or secondary mitochondrial defects.
RRFs
A histopathological finding in a muscle biopsy, featuring abnormal accumulation of mitochondria using the Gomori trichrome stain.
RBFs
Muscle fiber morphology showing subsarcolemmal mitochondrial aggregates (which could be examined as such by way of SDH staining).
COX-negative Fibers
Histochemical analysis demonstrates an absence of COX activity in muscle fibers, indicating a mitochondrial respiratory chain deficiency.
Therapeutics Development for Primary Mitochondrial Diseases
| Drugs |
Target Disease |
Target |
Development Stage |
| Elamipretide |
Mitochondrial DNA Depletion |
Cardiolipin |
Phase III |
| Cysteamine Bitartrate |
Leigh Syndrome |
Cystine |
Phase II |
| NFS-02 |
Leber Hereditary Optic Neuropathy |
ND4 gene |
Phase I/II |
| NR082 |
Leber Hereditary Optic Neuropathy |
ND4 gene |
Phase I/II |
| PYC-001 |
Autosomal Dominant Optic Atrophy |
OPA1 |
Phase I/II |
| Vatiquinone |
Friedreich's Ataxia |
15-Lipoxygenase |
Phase III |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Using our extensive knowledge in mitochondrial biology, state-of-the-art multi-omics technologies, and proven records in translation research, we offer an all-in-one bespoke service. Our solution includes biomarker identification and mitochondrial analysis services, as well as preclinical screening and validation of therapeutic candidates, development of physiologically-relevant in vitro and in vivo disease models designed to meet the requirements of primary mitochondrial disease drug developers and researchers.
Multiple Primary Mitochondrial Disease Research
Protheragen's group develops and conducts custom-made research programs on a large series of primary mitochondrial diseases, including severe systemic mitochondrial diseases and organ-specific mitochondrial diseases. Services are individualized to facilitate accurate modelling and therapy development for researchers who focus on genetic defects in nuclear DNA (e.g., POLG, TK2, or SURF1) or mitochondrial mtDNA.
Diagnostics and Therapeutics Development for Primary Mitochondrial Diseases
For this model of primary mitochondrial diseases, we provide in-depth and customized disease model development services, including precise cell-based models and physiologically relevant animal models. Moreover, our end-to-end capacity results in disease models with high specificity, accuracy in recapitulating genetic defects, biochemical malfunction, and phenotypic manifestation, and offers stable platforms for testing the target validity, mechanistic investigation, or therapeutic efficacy.
| Model Name |
Disease Association |
Modeling Method |
| Taz-KD Model |
Barth Syndrome |
Knockdown |
| Taz-KO Model |
Barth Syndrome |
Knockout |
| Ndufs4-KO Model |
Leigh Syndrome |
Knockout |
| Surf1-KO Model |
Leigh Syndrome |
Knockout |
| Tk2-KO Model |
Mitochondrial DNA Depletion Syndrome |
Knockout |
| Opa1-KO Model |
Autosomal Dominant Optic Atrophy |
Knockout |
| Tfam-KO Model |
Mitochondrial Myopathy |
Knockout |
| … |
… |
… |
Contact Us
Combining cutting-edge science with the most innovative technologies, Protheragen provides the essential tools and expertise to advance your primary mitochondrial disease research and therapeutic programs. Our end-to-end solutions extend to critical preclinical stages, such as complete pharmacokinetic analysis and toxicity assessment to produce reliable data. De-risk development and speed your drug candidate to the application with our end-to-end, integrated services from discovery through safety assessment. For a customized solution for your specific project requirements, please contact our experts for a detailed consultation.
Reference
- Conti, Federica et al. "Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?" International journal of molecular sciences 24.23 (2023): 16746.
