Therapeutic Options in Hereditary Optic Neuropathies

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations

Hearing dysfunction in a large family affected by dominant optic atrophy (OPA8-related DOA): A human model of hidden auditory neuropathy

Hidden auditory neuropathy is characterized by reduced performances in challenging auditory tasks with the preservation of hearing thresholds, resulting from diffuse loss of cochlear inner hair cell (IHC) synapses following primary degeneration of unmyelinated terminals of auditory fibers. We report the audiological and electrophysiological findings collected from 10 members (4 males, 6 females) of a large Italian family affected by dominant optic atrophy, associated with the OPA8 locus, who complained of difficulties in understanding speech in the presence of noise. The patients were pooled into two groups, one consisting of 4 young adults (19\u201350 years) with normal hearing thresholds, and the other made up of 6 patients of an older age (55\u201372 years) showing mild hearing loss. Speech perception scores were normal in the first group and decreased in the second. Otoacoustic emissions (OAEs) and cochlear microphonics (CMs) recordings were consistent with preservation of outer hair cell (OHC) function in all patients, whereas auditory brainstem responses (ABRs) showed attenuated amplitudes in the first group and severe abnormalities in the second. Middle ear acoustic reflexes had delayed peak latencies in all patients in comparison with normally hearing individuals. Transtympanic electrocochleography (ECochG) recordings in response to 0.1 ms clicks at intensities from 120 to 60 dB peak equivalent SPL showed a reduction in amplitude of both summating potential (SP) and compound action potential (CAP) together with delayed CAP peak latencies and prolonged CAP duration in all patients in comparison with a control group of 20 normally hearing individuals. These findings indicate that underlying the hearing impairment in OPA8 patients is hidden AN resulting from diffuse loss of IHCs synapses. At an early stage the functional alterations only consist of abnormalities of ABR and ECochG potentials with increased latencies of acoustic reflexes, whereas reduction in speech perception scores become apparent with progression of the disease. Central mechanisms increasing the cortical gain are likely to compensate for the reduction of cochlear input

OpenSeesPy-based web application for pushover curve computation of RC bridge piers subject to arbitrarily non-uniform corrosion patterns

Existing reinforced concrete (RC) bridge piers are often subject to complex spatially non-uniform steel corrosion patterns typically due to water percolation and exposition to environmental agents. This produces degradation of strength and ductility of the pier, which may significantly influence the seismic performances of bridges. The computation of pushover curves of corroded RC piers can be carried out by fiber-beam-column elements combined with suitable degradation laws for the uniaxial materials. For this purpose, a multi-level fiber-based modeling procedure is proposed based on a partition of the pier into zones characterized by different cross-sections with fiber discretizations reproducing the sectional deterioration pattern. A web application based on OpenSeesPy is defined to implement this procedure. This includes an interface developed by React JS and Boostrap V5 and an APIs layer based on the Flask framework. Through the interface, users can insert the parameters needed for the structural response simulation, which is, then, performed by employing the numerical procedure developed in Python. At the end of the computation, users can visualize and download the results or vary the input parameters to perform new simulations. The web application runs in a Docker container, making it easy to deploy on cloud platforms or on-premises solutions. Numerical simulations of real specimens affected by material deterioration are performed

Progressive ataxia with oculo-palatal tremor and optic atrophy

The final publication is available at Springer via doi: 10.​1007/​s00415-013-7136-

SPADA: A project to study the effectiveness of shielding materials in space

The SPADA (SPAce Dosimetry for Astronauts) project is a part of an extensive teamwork that aims to optimize shielding solutions against space radiation. Shielding is indeed an irreplaceable tool to reduce exposure of crews of future Moon and Mars missions. We concentrated our studies on two flexible materials, Kevlar R� and Nextel R,� because of their ability to protect human space infrastructures from micrometeoroids. We measured radiation hardness of these shielding materials and compared to polyethylene, generally acknowledged as the most effective space radiation shield with practical applications in spacecraft. Both flight test (on the International Space Station and on the Russian FOTON M3 rocket), with passive dosimeters and accelerator-based experiments have been performed. Accelerator tests using high-energy Fe ions have demonstrated that Kevlar is almost as effective as polyethylene in shielding heavy ions, while Nextel is a poor shield against high-charge and -energy particles. Preliminary results from spaceflight, however, show that for the radiation environment in low-Earth orbit, dominated by trapped protons, thin shields of Kevlar and Nextel provide limited reduction

Longitudinal Study of Optic Disk Perfusion and Retinal Structure in Leber's Hereditary Optic Neuropathy

PURPOSE. The purpose of this study was to evaluate optic disk perfusion and neural retinal structure in patients with subacute Leber's hereditary optic neuropathy (LHON) and LHON carriers, as compared with healthy controls. METHODS. This study included 8 patients with LHON in the subacute stage, 10 asymptomatic carriers of a LHON-associated mitochondrial DNA mutation, and 40 controls. All subjects underwent measurement of the retinal nerve fiber layer (RNFL) thickness, the ganglion cell-inner plexiform layer (GCIPL) thickness using optical coherence tomography and optic disk microvascular perfusion (Mean Tissue [MT]) using laser speckle flowgraphy (LSFG). Patients were re-examined after a median interval of 3 months from the baseline visit. RESULTS. LHON carriers had higher values of RNFL thickness, GCIPL thickness, and disk area than controls (P < 0.05), whereas MT was not different between the two groups (P = 0.936). Median MT and RNFL thickness were 32% and 15% higher in the early subacute stage of the disease than in controls (P < 0.001 and P = 0.001). MT declined below the values of controls during the late subacute stage (P = 0.024), whereas RNFL thickness declined later during the dynamic stage (P < 0.001). GCIPL thickness was lower in patients with LHON than in controls independently of the stage of the disease (P < 0.001). CONCLUSIONS. The high blood flow at the optic disk during the early subacute stage may be the consequence of vasodilation due to nitric oxide release as compensation to mitochondrial impairment. Optic disk perfusion as measured by LSFG is a promising biomarker for LHON diagnosis and monitoring as well as an objective outcome measure for assessing response to therapies

Capturing the Pattern of Transition From Carrier to Affected in Leber Hereditary Optic Neuropathy

center dot PURPOSE: To capture the key features patterning the transition from unaffected mutation carriers to clinically affected Leber hereditary optic neuropathy (LHON), as investigated by optical coherence tomography. center dot DESIGN: Observational case series. center dot METHODS: Four unaffected eyes of 4 patients with LHON with the first eye affected were followed across conversion to affected, from 60 days before to 170 days after conversion. The primary outcome measures were multiple timepoints measurements of peripapillary retinal nerve fiber layer (RNFL) thickness for temporal emiside of the optic nerve (6 sectors from 6-11, clockwise for the right eye and counterclockwise for the left eye) in all patients and nasal emi-macular RNFL and ganglion cell layer (GCL) thickness in 2 patients. center dot RESULTS: While the presymptomatic stage was characterized by a dynamic thickening of sector 8, the beginning of the conversion coincided with an increase in the thickness of the sectors bordering the papillo-acular bundle (6 and 7 for the inferior sectors, 10 and 11 for the superior sectors) synchronous with the thinning of sectors 8 and then 9. Conversely, the GCL did not undergo significant changes until the onset of visual loss when a significant reduction of thickness became evident. center dot CONCLUSION: In this study we demonstrated that the thinning of sector 8 can be considered the structural hallmark of the conversion from the presymptomatic to the affected state in LHON. It is preceded by its own progressive thickening extending from th

Diffusion tensor imaging mapping of brain white matter pathology in mitochondrial optic neuropathies

BACKGROUND AND PURPOSE: Brain white matter is frequently affected in mitochondrial diseases; optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy are the most frequent mitochondrial monosymptomatic optic neuropathies. In this observational study, brain white matter microstructure was characterized by DTI in patients with optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy, in relation to clinical and genetic features. MATERIALS AND METHODS: Nineteen patients with optic atrophy gene 1-autosomal dominant optic atrophy and 17 with Leber hereditary optic neuropathy older than 18 years of age, all genetically diagnosed, and 19 healthy volunteers underwent DTI by using a 1.5T MR imaging scanner and neurologic and ophthalmologic assessments. Brain white matter DTI metrics were calculated for all participants, and, in patients, their correlations with genetics and clinical findings were calculated. RESULTS: Compared with controls, patients with optic atrophy gene 1-autosomal dominant optic atrophy had an increased mean diffusivity in 29.2% of voxels analyzed within major white matter tracts distributed throughout the brain, while fractional anisotropy was reduced in 30.3% of voxels. For patients with Leber hereditary optic neuropathy, the proportion of altered voxels was only 0.5% and 5.5%, respectively, of which half was found within the optic radiation and 3.5%, in the smaller acoustic radiation. In almost all regions, fractional anisotropy diminished with age in patients with optic atrophy gene 1-autosomal dominant optic atrophy and correlated with average retinal nerve fiber layer thickness in several areas. Mean diffusivity increased in those with a missense mutation. Patients with Leber hereditary optic neuropathy taking idebenone had slightly milder changes. CONCLUSIONS: Patients with Leber hereditary optic neuropathy had preferential involvement of the optic and acoustic radiations, consistent with trans-synaptic degeneration, whereas patients with optic atrophy gene 1-autosomal dominant optic atrophy presented with widespread involvement suggestive of a multisystemic, possibly a congenital/developmental, disorder. White matter changes in Leber hereditary optic neuropathy and optic atrophy gene 1-autosomal dominant optic atrophy may be exploitable as biomarkers. ABBREVIATIONS: DOA autosomal dominant optic atrophy; FA fractional anisotropy; LHON Leber hereditary optic neuropathy; MD mean diffusivity; OPA1 optic atrophy gene 1 ;O R optic radiation; RNFL retinal nerve fiber layer; TBSS tract-based spatial statistic

Longitudinal Study of Optic Disk Perfusion and Retinal Structure in Leber's Hereditary Optic Neuropathy

Purpose: The purpose of this study was to evaluate optic disk perfusion and neural retinal structure in patients with subacute Leber's hereditary optic neuropathy (LHON) and LHON carriers, as compared with healthy controls. Methods: This study included 8 patients with LHON in the subacute stage, 10 asymptomatic carriers of a LHON-associated mitochondrial DNA mutation, and 40 controls. All subjects underwent measurement of the retinal nerve fiber layer (RNFL) thickness, the ganglion cell-inner plexiform layer (GCIPL) thickness using optical coherence tomography and optic disk microvascular perfusion (Mean Tissue [MT]) using laser speckle flowgraphy (LSFG). Patients were re-examined after a median interval of 3 months from the baseline visit. Results: LHON carriers had higher values of RNFL thickness, GCIPL thickness, and disk area than controls (P < 0.05), whereas MT was not different between the two groups (P = 0.936). Median MT and RNFL thickness were 32% and 15% higher in the early subacute stage of the disease than in controls (P < 0.001 and P = 0.001). MT declined below the values of controls during the late subacute stage (P = 0.024), whereas RNFL thickness declined later during the dynamic stage (P < 0.001). GCIPL thickness was lower in patients with LHON than in controls independently of the stage of the disease (P < 0.001). Conclusions: The high blood flow at the optic disk during the early subacute stage may be the consequence of vasodilation due to nitric oxide release as compensation to mitochondrial impairment. Optic disk perfusion as measured by LSFG is a promising biomarker for LHON diagnosis and monitoring as well as an objective outcome measure for assessing response to therapies