Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome

Ferrari, Michele; Jain, Isha H.; Goldberger, Olga; Rezoagli, Emanuele; Thoonen, Robrecht; Cheng, Kai-Hung; Sosnovik, David E.; Scherrer‐Crosbie, Marielle; Mootha, Vamsi K.; Zapol, Warren M.

doi:10.1073/pnas.1621511114

Cited by 133 publications

(138 citation statements)

References 38 publications

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“…Among these subunits, mutations in the genomic DNA of the gene encoding the NADHubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4) cause Leigh syndrome in humans. [7][8][9] In Ndufs4 KO mice, maturation of the C-I assembly is disturbed, resulting in immature C-I complex formation with decreased C-I activity, although other RC components remain intact. 6 Ndufs4 knockout (KO) mice phenocopy the human Leigh syndrome; hence, these mice have been used for mitochondrial disease research.…”

Section: Introductionmentioning

confidence: 99%

Higd1a improves respiratory function in the models of mitochondrial disorder

et al. 2019

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oxidoreductase iron-sulfur protein 4; NSUN3, NOL1/NOP2/Sun domain-containing protein 3; OCR, oxygen consumption rate; OG, n-octyl-β-D-glucoside; OXPHOS, oxidative phosphorylation; RC, respiratory chain; ROS, reactive oxygen species. Correspondence AbstractThe respiratory chain (RC) transports electrons to form a proton motive force that is required for ATP synthesis in the mitochondria. RC disorders cause mitochondrial diseases that have few effective treatments; therefore, novel therapeutic strategies are critically needed. We previously identified Higd1a as a positive regulator of cytochrome c oxidase (CcO) in the RC. Here, we test that Higd1a has a beneficial effect by increasing CcO activity in the models of mitochondrial dysfunction. We first demonstrated the tissue-protective effects of Higd1a via in situ measurement of mitochondrial ATP concentrations ([ATP] mito ) in a zebrafish hypoxia model. Heartspecific Higd1a overexpression mitigated the decline in [ATP] mito under hypoxia and preserved cardiac function in zebrafish. Based on the in vivo results, we examined the effects of exogenous HIGD1A on three cellular models of mitochondrial disease;notably, HIGD1A improved respiratory function that was coupled with increased ATP synthesis and demonstrated cellular protection in all three models. Finally, enzyme kinetic analysis revealed that Higd1a significantly increased the maximal 1860 | NAGAO et Al.

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Section: Introductionmentioning

confidence: 99%

Higd1a improves respiratory function in the models of mitochondrial disorder

et al. 2019

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“…At the pre-clinical level, strategies based either on a pharmacological inhibition of mTOR or exposures to hypoxic conditions have provided remarkable therapeutic effects as well as important insights into the disease mechanism but their transposability in the clinic is limited (Johnson et al, 2013;Johnson et al, 2015;Jain et al, 2016;Ferrari et al, 2017). Gene replacement therapy using an AAV9 vector has also been attempted in Ndufs4 KO neonates but resulted in marginal benefits (Quintana et al, 2012;Di Meo et al, 2017).…”

Section: Several Mutations Have Been Associated To Ls Including Some mentioning

confidence: 99%

Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome

Reynaud-Dulaurier

Benegiamo

Marrocco

et al. 2020

Preprint

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Mutations in nuclear-encoded mitochondrial genes are responsible for a broad spectrum of disorders among which Leigh syndrome (LS) is the most common in infancy. No effective therapies are available for this severe disease mainly because of the limited capabilities of the standard adeno-associated viral (AAV) vectors to transduce both peripheral organs and the central nervous system (CNS) when injected systemically in adults.Here, we used the brain-penetrating AAV-PHP.B vector to reinstate gene expression in the Ndufs4 KO mouse model of LS. Intravenous delivery of an AAV.PHP.B-Ndufs4 vector in 1-month old KO mice restored mitochondrial complex I activity in several organs including the CNS. This gene replacement strategy extended lifespan, rescued metabolic parameters, provided behavioral improvement, and corrected the pathological phenotype in the brain, retina, and heart of Ndufs4 KO mice. These results provide a robust proof that gene therapy strategies targeting multiple organs can rescue fatal neurometabolic disorders with CNS involvement. Keyword: Gene therapy, neurometabolic disease, mitochondria, AAV vector the guidelines of the European Directives (2010/63/EU) and the ARRIVE guidelines. They were reviewed and approved by the Italian Ministry of Health, Department of Public Health, Animal Health, Nutrition and Food Safety, in accordance with the law on animal experimentation (article7; D.L. 116/92; protocol number: 26/2014). Adeno-associated viral (AAV) vector production and injectionThe plasmid containing the Ndufs4-IRES-GFP cassette under the control of the CMVchicken b-actin (CBA) promoter was provided by Pr. Palmiter (University of Washington School of Medicine) (Quintana et al., 2012). The AAV.PHP.B plasmid was provided by Dr. Gradinaru (California Institute of Technology) (Deverman et al.,

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“…In general, time of starting treatment is crucial, and the effect of intervention at an early stage is more remarkable than at a late stage. Unexpectedly, hypoxia (normobaric 11% O 2 ) was recently reported to reverse established neurological lesions in Ndufs4 mice with late stage LS . Researchers are optimistic that the same benefits may apply in humans, given that oxygen pressure and innate pulmonary physiological parameters are conserved across the species.…”

Section: Future Therapeutic Strategiesmentioning

confidence: 99%

Management of Leigh syndrome: Current status and new insights

et al. 2018

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Leigh syndrome (LS) is an inherited mitochondrial encephalopathy associated with gene mutations of oxidative phosphorylation pathway that result in early disability and death in affected young children. Currently, LS is incurable and unresponsive to many treatments, although some case reports indicate that supplements can improve the condition. Many novel therapies are being continuously tested in pre-clinical studies. In this review, we summarize the genetic basis of LS, current treatment, pre-clinical studies in animal models and the management of other mitochondrial diseases. Future therapeutical strategies and challenges are also discussed.

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Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome

Cited by 133 publications

References 38 publications

Higd1a improves respiratory function in the models of mitochondrial disorder

Higd1a improves respiratory function in the models of mitochondrial disorder

Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome

Management of Leigh syndrome: Current status and new insights

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