From: Current advances in gene therapy of mitochondrial diseases
Delivered gene | Description of model | Vector and route of administration | Effect | Reference |
---|---|---|---|---|
Full cDNA of human wild-type TYMP | Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) murine model (Double Tymp/Upp1 knockout) Represents nDNA mutation | Single intravenous (IV) administration of haematopoietic donor-derived cells with TYMP coding sequence transduced by lentiviral vector | Restoration of thymidine phosphorylase (TP) activities in peripheral blood cells of treated mice Decrease of plasma thymidine and deoxyuridine concentrations to levels in the range of wild-type mice | [113] |
Full cDNA of human wild-type TYMP | Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) murine model (Double Tymp/Upp1 knockout) Represents nDNA mutation | Single IV injection (tail vein) of AAV2/8-TBG-hcTYMP | Dose-dependent restoration of TP activity in the liver and improvement of biochemical abnormalities in the liver and blood (34Â weeks after treatment) | [114], |
Full cDNA of human wild-type TYMP | Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) murine model (Double Tymp/Upp1 knockout) Represents nDNA mutation | Single IV injection (tail vein) of AAV2/8-TBG-hcTYMP | Dose-dependent restoration of TP activity in the liver and improvement of biochemical abnormalities in the liver and blood (21Â months after treatment) | [115] |
Full cDNA of human wild-type TYMP | MNGIE murine model (Double Tymp/Upp1 knockout + chronic oral administration of thymidine and deoxyuridine) | Single IV injection (tail vein) of liver-targeted AAV vectors (AAV-TBG, AAV-AAT, or AAV-HLP) | Restoration of TP activity in liver Amelioration of biochemical abnormalities Improvement of motor functions AAV-AAT and AAV-HLP treatment prevented ventricular enlargement Normalization of the mitochondrial dNTP balance | [116] |
cDNA of mouse wild-type Slc25a46 | Slc25a46 knockout mice | Single IV injection (facial vein of pups) of neurotrophic AAV–PHP.B vector | Prolongation of lifespan Increase of bodyweight Attenuation of central nervous system defects and ataxia Attenuation of optic atrophy Restoration of mitochondrial morphology and activity in various tissues | |
cDNA of human wild type OPA1 | Hemizygous OPA1 ± mice carrying human OPA1 transgene with c.2708_2711delTTAG mutation | Single IVT injection of AAV2 serotype 2 vector | Modest restoration of visual acuity Prevention of loss of retinal ganglion cells number | [121] |
cDNA of codon-optimized versions of human OPA1 isoform 1 and 7 | Wild type mice with rotenone-induced retinal degeneration | Single IVT injection of AAV2 serotype 2 vector | Improvement of spatial visual function | [123] |
cDNA of Opa1 long isoform with 11 residues (190–200) deleted in the S1 cleavage site (Opa1-ΔS1) | Rats with ischemia–reperfusion retinal injury | Single IVT injection of AAV | Normalization of the ischemia–reperfusion-induced downregulation of β-tubulin ΙΙΙ and Brn3a Inhibition of the retinal thickness and the cell loss in the ganglion cells layer Attenuation of elevation of receptor-interacting protein 3 and cleavage of caspase 3 | [124] |
cDNA of human OPA1 long isoform with deletion of the S1 cleavage site (OPA1-v1ΔS1) | Rats with focal cerebral ischemia–reperfusion injury | Single IVT injection of AAV | Decrease of neurological deficit and attenuation of infarct volume Restoration of mitochondrial cristae morphology and mitochondrial length Preservation of mitochondrial integrity | [125] |
Human cDNA of wild-type NDUFS4 | Constitutive Ndufs4 − / − mouse model developing a rapidly progressive encephalopathy, starting ~ 40 days after birth | IV or intracerebroventricular (ICV) or IV + ICV injections of AAV2/9 | Systemic AAV2/9-hNDUFS4 restores complex I assembly and activity in peripheral tissues but does not ameliorate the clinical phenotype ICV injections of AAV2/9-hNDUFS4 slightly ameliorate the clinical phenotype in newborn Ndufs4 − / − mice Double IV + ICV injections in newborns of AAV2/9-hNDUFS4 ameliorate the clinical phenotype and increases lifespan of Ndufs4 − / − mice | [127] |
Human cDNA of wild-type NDUFS4 | Constitutive Ndufs4 − / − mouse model developing a rapidly progressive encephalopathy, starting ~ 40 days after birth | Single IV (tail vein in adult mice, temporal vein in newborns) of AAV-PHP.B | Prolongation of the lifespan, improvement of motor functions and complex I assembly in adult mice Absence of effect and typical disease progression in newborns | [128] |
Human cDNA of wild-type NDUFS4 | Constitutive Ndufs4 − / − mouse model developing a rapidly progressive encephalopathy, starting ~ 40 days after birth | Single IV injection (retroorbital sinus) | Increase of survival rate and body weight Improvement of motor functions Prevention of neuronal and glial pathology Improvement of retinal function | [129] |
cDNA of murine wild-type Fdxr | Fdxr R389Q/R389Q mice | IV injections of AAV-PHP.B vector (temporal facial vein of neonatal mice) | Alleviation of neuronal gliosis and neurodegeneration in the CNS Mitigation of the optic atrophy, reduction of the movement disorders and sensory neuropathy Improvement of mitochondrial function, decrease of iron overload | |
cDNA of human wild-type ETHE1 | Ethe1 -/- mice | Intra-cardiac injections of AAV2/8 | Increase of survival rates and body weight Attenuation of biochemical abnormalities | [133] |
cDNA of human TK2 | Tk2KI mice | Single IV injection of AAV9 or sequential IV injection of AAV9 and AAV2 | enhanced replacement therapy with pyrimidine deoxynucleosides delaying disease onset and extending lifespan in mice | [136] |