Emerging model systems and treatment approaches for Leber's hereditary optic neuropathy: Challenges and opportunities

From Transcriptomics to Treatment in Inherited Optic Neuropathies

“…Thus, this presents an unmet need to identify the novel pathways and genes involved to which comparative transcriptomics is particularly suited. Whilst direct access to RGCs and patient tissues is limited, cellular and mouse model systems [ 7 , 29 , 30 ] have developed in recent years into powerful platforms with which to perform transcriptomic studies (and, more importantly, validate and investigate their findings). For example, in vivo neuro-retinal tissue can easily be visualized (if not directly sampled) at the cellular level with techniques such as optical coherence tomography (OCT), and there are well defined metrics of RGC function at the behavioral (acuity) [ 31 ], reflex (pupillary) [ 32 ], and electrophysiological levels [ 33 ].…”

“…For example, in vivo neuro-retinal tissue can easily be visualized (if not directly sampled) at the cellular level with techniques such as optical coherence tomography (OCT), and there are well defined metrics of RGC function at the behavioral (acuity) [ 31 ], reflex (pupillary) [ 32 ], and electrophysiological levels [ 33 ]. To compliment this, induced pluripotent stem cell (iPSC) RGC models derived from LHON and DOA patient tissues have proved invaluable for molecular investigations [ 7 ]…”

“…However, the relatively large metabolic demand for these specialized cells and their unique anatomy are thought to be important contributory factors. RGCs have long axonal segments which lack myelin throughout their intraocular course but gain a myelin sheath on exiting the eye beyond the lamina cribosa [ 7 , 8 ]. As the only nervous tissue visible in vivo and with increasingly sophisticated cell culture techniques [ 9 , 10 ], RGCs present a powerful system in which to interrogate mitochondrial dysfunction and the pathways that ultimately lead to cell loss and disease development.…”

“…As monogenetic conditions where mitochondrial function is disturbed, both LHON and DOA can mitigate some of these challenges and act as useful model diseases of more complex neurodegenerative disease processes. LHON is a primary mitochondrial DNA (mtDNA) disorder, with the majority of cases caused by one of three point mutations—namely, m.3460G>A in the MT-ND1 gene, m.11778G>A in the MT-ND4 gene, and m.14484T>C in the MT-ND6 gene—all of which encode for essential subunits of mitochondrial complex I [ 3 , 7 , 14 , 15 , 16 ]. LHON is additionally interesting due to its predilection to manifest in males and its marked incomplete penetrance—both of which could perhaps have origins in transcriptomic differences.…”

Development of mitochondrial replacement therapy: A review

“… MT-ND1; MT-ND4; MT-ND4L; MT-ND6; MT-ND5; Cytochrome-b (MT-CYB); Cytochrome-c oxidase (MT-CO3); tRNA (threonine) (MT-TT); tRNA (Glutamic acid) (MT-TE) 1/30,0000 Tai (2016) ; Davison et al. (2019) ; Bahr et al. (2020) 5 Neurogenic Ataxia and Retinitis Pigmentosa (NARP) Mt-8993T > G/C; c.1092+5G > A Dementia, seizures, ataxia, sensory neuropathy and retinitis pigmentosa.…”