Purpose: To demonstrate safety and efficacy of allotopic human ND4 for treatment of Leber's hereditary optic neuropathy (LHON) mouse model harboring G11778A mitochondrial mutation. Methods: We induced LHON in mice by intravitreal injection of mutant (G11778A) human ND4 DNA responsible for most cases of LHON that was directed to mitochondria using an AAV2 vector to which we appended a mitochondrial targeting sequence to the VP2 capsid. We then attempted rescue of visual loss using our test article (ScAAV2-P1ND4v2) containing a synthetic nuclear encoded G11778G ND4 gene that was allotopically expressed. Control mice were either un-injected or received AAV2-GFP or AAV2-mCherry. We performed RT-PCR and confocal microscopy at 2 weeks post injection. Pattern electroretinograms (PERGs), SD-OCT, histology and TEM were performed. For toxicology and biodistribution studies the test article was administered intravitreally to rats and rhesus macaques at different doses. Results: Mutant and wild-type ND4 were efficiently expressed in the mitochondria of retinal ganglion cells. Visual function assessed by PERGs and retinal structure by SD-OCT showed a significant rescue by the test article. Histology and ultrastructural analysis confirmed loss of RGCs and demise of axons was prevented by ScAAV2-P1ND4v2. Rat and nonhuman primate biodistribution studies showed vector spread outside the injected eye into spleen and lymph nodes was minimal. Histopathology of tissues and organs including the eyes was comparable to uninfected and saline injected eyes. Conclusions: Allotopically expressed wild-type ND4 prevents the phenotype induced by G11778A mitochondrial DNA with a toxicology profile acceptable for testing in a phase I clinical trial.
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 11 December 2014.
All research outputs
#22,694,404
of 27,782,313 outputs
Outputs from Investigative Ophthalmology & Visual Science
#6,898
of 8,762 outputs
Outputs of similar age
#206,110
of 276,494 outputs
Outputs of similar age from Investigative Ophthalmology & Visual Science
#102
of 137 outputs
Altmetric has tracked 27,782,313 research outputs across all sources so far. This one is in the 10th percentile – i.e., 10% of other outputs scored the same or lower than it.
So far Altmetric has tracked 8,762 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.1. This one is in the 12th percentile – i.e., 12% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 276,494 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 13th percentile – i.e., 13% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 137 others from the same source and published within six weeks on either side of this one. This one is in the 13th percentile – i.e., 13% of its contemporaries scored the same or lower than it.
