TREATMENT LHON

1. TREATMENT LHON
Pharmacology Treatment
Patients with mitochondrial disease, including LHON, are usually prescribed ubiquinone (also
known as coenzyme Q10), a component of RC3 [1]. A molecular analogue of ubiquinone with
enhanced bioavailability called idebenone has been confirmed. RHODOS (Rescue of Hereditary
Optic Disease Outpatient Study) randomized and placebo-controlled, double-blind trial with 85
patients, the group given high-dose idebenone (900 mg) for 24 weeks had better vision than
placebo controls, without signs of adverse drug reactions. Patients with early-stage disease seem
to be the most benefit
There is no definitively effective treatment available for LHON. It has been reported that
idebenone, a short-chain derivative of coenzyme Q10, is a potential agent for treating LHON7, but
its treatment efficiency is therapeutic. Idebenone and vitamin B12 therapy were reported to be
effective in some patients8, but failed in others. Recent studies have shown that the para-
benzoquinone analogue of coenzyme Q10 and idebenone, EPI-743, holds promise for improving
pharmacological properties; there was a marked improvement in some of the visual function
parameters tested. Nevertheless, new methods in the treatment of LHON still need to be explored
[2]
Gene Therapy
One such alternative method is gene therapy The goal of gene therapy for LHON, and other
mitochondrial diseases, is to rescue mitochondrial function to a level sufficient to at least relieve
the symptoms of, if not cure, the target disease by supplementing the intact/wild-type allele from
dysfunctional genes above the clinical threshold for a normal physiological phenotype. The
advantage of the genetic simplicity of mtDNA, however, is countered by its inaccessibility deep
within the double-membrane mitochondrial organelle, which, normally, allows the passage of only
very small molecules, such as ATP and proteins smaller than 10 kDa [3].

2. There are several very promising lines of current research aimed at developing safe and effective
biological strategies to reconstitute ND4-deficient mitochondria in RGCs with wild-type ND4,
with the long-term goal of producing a drug for LHON. Biological approaches to mtDNA delivery
with increasing fluency are being developed. Several research groups have included mitochondrial
targeting signal peptide (MTS) tags used by cells in their strategy to deliver molecules to
mitochondria, such as the MTS-conjugated peptide nucleic acid carrier , MTS-conjugated
lysine/histidine peptide carrier, and MTS-conjugated AVV carriers . This approach has been
reported to provide dramatic protection from RGC loss in animal models. In particular, Yu et al
demonstrated long-term expression of ND4, the mutation responsible for the majority of cases of
LHON, in mouse cells transfected with human ND4 via AVV carriers in which the viral capsid of
VP2 has been modified to include MTS.
Several research groups have addressed the problem of mitochondrial targeting by focusing on
introducing the ND4 product into the mitochondria after expression rather than the whole vector.
This approach, known as allotopic expression, is based on the premise that ND4 transcribed in the
nucleus is transcribed in the cytoplasm and then sent to the mitochondria via MTS which is
decoded in the same way that mitochondrial intrinsic proteins encoded by nuclear genes are
delivered to mitochondria.
Cwerman-Thibault et al. developed an AAV2/2-ND4 delivery system using MTS from COX10.
They demonstrated efficient incorporation of the ND4 protein into RC1 of RGCs in 8-week-old
mice. In addition, LHON model mice treated with AAV2/2-ND4 exhibit attenuated RGC
degradation and preservation of visual function.
Following the promising results above, Feuer and colleagues conducted a phase I safety trial for
allotopic AAV2-ND4 gene therapy in human patients who were legally blind due to LHON caused
by the 11778G[A ND4 mutation. Of the five patients in the study, one experienced temporary
minor adverse events in the injected eye, including increased intraocular pressure and
subconjunctival hemorrhage. No negative outcomes, such as further loss of vision or major side
effects, were observed. Ninety days after the procedure, Best Corrected Visual Acuity (BCVA)
remained unchanged in three patients, but had improved significantly in two patients.
GenSight Biologics, Paris, France, in three phase 3 studies of LHON demonstrated that rAAV2/2-
ND4 was safe and well tolerated 2 years after a single unilateral intravitreal administration.

3. However, some patients experience early improvement in visual acuity, color vision, and contrast
sensitivity in the treated eye. The most common side effects during the study were mild anterior
chamber or vitreous inflammation and moderate elevation of intraocular pressure. All ocular
adverse events resolved with standard therapy and no visual sequelae occurred [4].
REFERENCES
1. Cuneyt Karaarslan . Leber’s Hereditary Optic Neuropathy as a Promising Disease for Gene
Therapy Development . 2019. 36:3299–3307. https://doi.org/10.1007/s12325-019-01113-
2
2. Jang Y, Lim K. Recent advances in mitochondria- targeted gene delivery. Molecules.
2018;23(9): E2316.
3. Bae Y, Jung MK, Song SJ, et al. Functional nano- some for enhanced mitochondria-
targeted gene delivery and expression. Mitochondrion. 2017;37: 27–40.
4. Vignal S, Uretsky S, Fitoussi S, et al. Safety of rAVV2/2-ND4 gene therapy for Leber’s
hereditary optic neuropathy. Ophthalmology. 2018;125(6): 945–7.