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International Foundation for Optic Nerve Disease

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IFOND projects update 2016

Below is Dr Alfredo Sadun's 2016 Brazil LHON progress report.


Brazil LHON Project
Alfredo A, Sadun, MD PhD- Principle Investigator
2016 Progress Report

Since 2001, we have conducted yearly field investigations with an international team to a remote area of Brazil. There, we have examined, by a variety of methods, hundreds of patients with Leber's Hereditary Optic Neuropathy (LHON).

Our investigations on LHON in Brazil continue to define this disease in publications and textbooks. While it was already known that mutations in the 11778 gene caused a defect of Complex I, we have demonstrated that it is not so much the bioenergetics problem that leads to blindness. Rather, it is the blockage of electron transport that leads to the overproduction of ROS. This changes the membrane potential of the mitochondria which, at a critical threshold, induces an opening of the mitochondrial pores that allows for Cyctochrome c to leave the mitochondria and enter the cell cytosol. This, in turn, causes death of the retinal ganglion cells. This wave of cell death and optic atrophy follows a sequence that we have mathematically modeled to be a function of the axon size. This explains the reason for optic nerve damage and blindness in our LHON patients. These and other investigations that the disease occurs when a trigger adds to the accumulation of reactive oxygen species (ROS) produced by the mtDNA mutation. We expect to soon begin new clinical trials, both with Gensight (viral vector genetic engineering) and with Stealth Pharmaceuticals (controlling the negative effects of ROS on the cardiolipin of mitochondria).

Great progress has also been made in understanding, quantitating and measuring the psychological reactions to abrupt bilateral loss of vision from LHON. We launched three studies to better assess this in 103 patients ages 14-65 who had all suffered rapid profound bilateral vision loss from LHON. Using an electronic survey system, we designed and implemented with novel approaches for anonymity, we evaluated the psychoscial consequences of rapid profound bilateral vision loss in adolescents, young adults, and middle-aged adults with LHON. We also examined the impact of low vision aids, and assessed the role of ophthalmologists as providers of emotional support for these patients. We investigated the effects of blindness on their inetrpersonal interactions and career goals using a validated 2` point psychometric response scale. Depression prevalence was evaluated with validated questions regarding DSM-V major depressive disorder symptomatology. Subjects were additionally asked about sources of emotional support and use of low vision aids.

We found that rapid onset blindness had a negative impact on psychosocial well-being in young and middle-aged individuals. Older age at time of diagnosis and depression were associated with more negative self-appraisals. The use of electronic vision aids was associated with enhanced psychosocial well-being. Ophthalmologists, in addition to managing the disease, served important roles in the emotional adaptation of these patients.

While it is true that clnical science proceeds by many small steps. the work in our labs (LA and Bologna) and the field investigations in Brazil, have amassed an amazing amount of data and new understandings. I think we're at the cusp of managing this terrible cause of blindess in the young.

As to the coming year: We plan another trip to Brazil in 2017. As before the trip will include clinical, psychophysical and OCT measures of many kinds. We will also obtain more electrophysiological evaluations as well as obtaining blood samples for serum biomarkers and for more mtDNA for Dr. Carelli's analysis in Bologna, Italy.

We remain very indebted to IFOND for the continued financial, organizational and general support of these projects. While IFOND has provided most of the funding for the yearly field investigations to Brazil for the study of LHON, it has also provided for funds and personnel that have enabled us to capitalize on new found knowledge and strategically integrate our various research studies. These investigations have ranged from molecular characerizations, to electron microscopy, to morphometry, to immunohistopathology, to clinical longitudinal studies, to clinical trials of new agents, to measurements of the psychological impacts of the disease. Thank you.

Alredo A. Sadun, MD, PhD
Thornton Endowed Chair
Doheny Eye Center and
Vice-Chair of Ophthalmology, UCLA

Link to Papers IFOND helped sponsor

Here find links to published peer reviewed papers acknowledging IFOND's help. This research helped stimulate a cascade of broad research on mitochondrial and optic nerve disease.

Efficient funding

IFOND is an extremely lean, all volunteer 501(c)(3) tax status registered nonprofit. We have no salaried associates. Our process minimizes costs and maximizes funding for researchers' direct, non administrative expenses. All donations are tax deductible in the United States of America. Our recent tax returns are searchable here e.g. latest IRS website listed year 2021 here. Tax Year 2022 Form 990EZ and Tax Year 2022 IRS Filing Acceptance . Also see here. Our scientific board includes many of the prominent world leading published researchers in optic neuropathies. If this big bang for your buck model appeals to you, please donate. If you are a researcher in optic neuropathy, we welcome your funding application.

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