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Table 2 Tested approaches for delivery of nuclear genes associated with MD

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 (34 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 (21 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

[117, 130]

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

[117, 130]

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]