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International Foundation for Optic Nerve Disease

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IFOND projects update 2015

The generous support of the donors to IFOND continues to allow important progress in investigations of Leber's Hereditary Optic Neuropathy (LHON). Since 2001 we have sponsored regular annual field trips to rural Brazil in order to study the largest LHON pedigree in the world. These investigations have been fully described in previous reports. They have also led to numerous peer-reviewed publications and Association for Research in Vision and Ophthalmology (ARVO) annual symposium presentations. These investigations and publications have changed the face of LHON as studied, taught and clinically treated. This is an outstanding achievement for the researchers who punch well above their weight on shoe string budgets and volunteer support.

Below is the report of the 2015 Brazil LHON project from Dr Alfredo Sadun [written in 2016].

Brazil LHON Project

Alfredo A. Sadun, MD, PhD- Principal Investigator

Progress Report: 2016

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).

With funding from the International Foundation for Optic Nerve Disease (IFOND), we were able to return for the 15th time to Brazil Oct 29 – Nov. 5, 2015. On that trip, I had the privilege to lead a team of about 25 international, Brazilian and local investigators to Colatina, Brazil. There were some issues that were largely logistic. For example, we brought new equipment for electrophysiology that had been designed to provide a new methodology to study Leber’s Hereditary Optic Neuropathy (LHON) in the field. The equipment was designed and built in Canada and assembled by my colleague, Rustum Karanjia, MD, PhD in Los Angeles. We then tested it on a few LHON patients in LA. After some glitches and new equipment, we packed the equipment and took it with us as luggage. Unfortunately, American Airlines made many mistakes with the baggage and lost it for 4 days. The good news is that the items were finally found and the electrophysiology equipment worked and, the recording were excellent enabling us to establish a new and powerful way to quantitate the disease in Brazil. We obtained recordings from about 30 patients.

Unfortunately, some of us felt ill during the last few days (fever and pharyngitis). One member of the team returned to Rome very sick and then was admitted to the ICU for hemorrhagic fever from a Dengue-like infection. This came from mosquito bites that our team was exposed to while in an endemic area. Again, the good news is that our physician scientists recovered and they are doing OK. Serological testing led to the surprising conclusion that this was a new Dengue like fever called Zika.

We continued to make great progress in the understanding and treatment of LHON. Specifically, we achieved 4 important objectives:

  1. We have now generated over 65 gigabytes of clinical and psychophysical information from about 300 patients and have done so every year for 15 years.

  2. We have run a small clinical trial using as treatment EPI-743. This trial has shown only modest results in regards to treatment. However, it was compromised in two important ways. Some patients were non-compliant. Brazilian customs held up the medication for over a month. But this unintended placebo effect demonstrated that the agent worked as everyone got worse of the medication. Furthermore, we found that patients were able to improve on EPI-743 even as much as 5 years after the initial loss of vision.

  3. We have already published 22 papers redefining the natural history of LHON. We have learned that carriers have subclinical signs and that Optical Coherent Tomography (OCT) can both anticipate the onset of the disease and follow the structural changes after visual loss.

  4. We have a much better understanding that there actually exist two versions of LHON. Type I occurs at an early age and abruptly. It leads to a rapid loss of vision with a lot of optic atrophy and is resistant to improvement. Type II occur at a later age (30-50) and comes on more slowly. Type II usually requires another risk factor.

Our yearly investigations in Brazil have already rewritten the textbooks on LHON. 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 Cytochrome 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). While it is true that clinical 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 blindness in the young.

We thank the more than two dozen volunteers, scientists, physicians and staff, who gave up a week of vacation time to promote this important yearly study. We also thank IFOND and other contributors who provided us the critical resources to accomplish this.

Alfredo 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. 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 here or also 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.

IFOND welcomes questions and comments
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