IFOND Projects, International Foundation for Optic Nerve Disease

In 2017 IFOND sponsored another field study in Brazil organised by Brazilian and international researchers. They are using objective measures of electrical activity, Phototic Negative Response (PhNR), in vivo as markers of cellular function in LHON and experiments. The team includes doctors Adriana Berezovsky, Solange Salomao, Nivea Cavascan, Arthur Fernandes from UNIFESP, and Dr. Milton Filho-Moraes and his team at the Colatina clinic together with our IFOND scientific board member, Dr Rustum Karanjia. They hope to establish an ideal protocol of outcome measures against which to test the effects of any purported treatment. See the detailed funding application grant proposal here.

Below is post study correspondence from Dr Rustum Karanja and Dr Solange Salomao:

In November 2017 the LHON Investigative Team was able to return to Colatina, Espirito Santo, Brazil to continue our research, thanks to the generous support of IFOND. The collaboration with the Soave-Brazil pedigree started in 2001 and IFOND has been instrumental in supporting the team efforts to understanding and treating this blinding disease. The latest visit to Brazil consisted of an international team of volunteer experts in electrophysiology and Neuro-ophthalmology. The team was able to reconnect with almost 50 members of the pedigree and other families afflicted by LHON. The data collected is a continuation of the work we have previously published on electrophysiology and LHON ( The Photopic Negative Response: An Objective Measure of Retinal Ganglion Cell Function in Patients With Leber's Hereditary Optic Neuropathy, IOVS 2017 May 1;58(6)). This data will be instrumental in understanding how new biomarkers can help us objectively follow patients with LHON and may hold some clues to help identify carriers who might be prone to conversion.

This effort would not have been possible without the continued support of the members of the Soave-Brazil pedigree, the team at Instituto de Olhos de Colatina, the team from the Federal University of São Paulo (UNIFESP), the Doheny Eye Institute and Doheny Eye Centers UCLA, and the Ottawa Eye Institute, with the support of Instituto da Visão (IPEPO) and IFOND.

Also, we are sponsoring a retinal biomarker study in Parkinson Disease and Alzheimer disease, both extremely important ailments with relevance to optic neuropathy and mitochondrial dysfunction. The research described here will be done by IFOND Board chair, Dr Ivan Bodis-Wollner MD DSc professor, neurologist, neuroscientist; Piotr Kozlowski MD, professor, neuropathologist; and Sofya Glazman MD research Coordinator.

Brazil LHON Project

Alfredo A. Sadun, MD, PhD- Principal Investigator

Progress Report: 2017

Since 2001, with the resources provided by the International Foundation of Optic Nerve Disease (IFOND), we have conducted another yearly field investigation 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).

We have been processing the data acquired on our yearly field trips to Colatina, Brazil 2001-2015. We were able to exploit three important sets of data acquired by our team of over 25 international, Brazilian and local investigators. This included a great deal of electrophysiological data acquired by bringing and leaving new equipment for retinal 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, built and brought down by my colleague, Rustum Karanjia, MD, PhD. The equipment was used in Colatina, Brazil on our giant pedigree and then set up again at the Fed. Univ. of Brazil in Sao Paulo under the auspices of Drs. Salomao and Berezovsky, allowing us to obtain control data on many other Brazilian patients age and gender-matched to those we examined in Colatina. Follow-up electrophysiology was also performed in Sao Paulo. A second set of new data came from Drs. Tran and Karanjia who arranged an electronic entry of all history as well as physical and psychophysical examinations. They brought this system down on laptop computers for a new entry of data that would allow more extensive comparison analysis. And we employed about 20 medical students to transfer data from old scanned in handwritten material to this new electronic format. With this system, we can do excel sheet analysis comparing any two or more elements of data.

The third data set consisted of our classic collection of information including annual OCTs, HVFs, color vision, contrast sensitivity, etc. Some of this is already in suitable digital form, and other parts need to be converted. Taken together, we hope that with the help of two post-docs, Anne Irvine and Kirsten Anderson, and under the supervision of Dr. Rustum Karanjia, this information can be used both to generate and test new hypothesis in regards to the pathophysiology, natural history and efficacy of treatments for LHON.

As of this date, we have published over 25 papers that, in the aggregate, completely redefine the natural history and treatment of LHON. Equally important, we have proposed new hypotheses regarding the fundamental pathophysiology of this and related diseases. These are being confirmed by us and other groups and this opens new avenues of approach for treatment of this devastating cause of bilateral blindness in young adults.

It was already known that mutations in the 11778 gene caused a defect of Complex I. But our work has demonstrated that it is not so much the bioenergetics problem that leads to blindness, but rather the blockage of electron transport that leads to the overproduction of reactive oxygen species. 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 produced by the mtDNA mutation. And we are now in the middle of three new clinical trials, with Gensight (viral vector genetic engineering) and with Stealth Pharmaceuticals (controlling the negative effects on the cardiolipin of mitochondria). The work in our labs and the field investigations in Brazil have amassed an amazing amount of data and new understandings.

We thank IFOND for support as well as the many physicians, scientists and staff who donated their time and energies.

Sincerely,

Alfredo

Alfredo A. Sadun, MD, PhD

Thornton Endowed Chair

Doheny Eye Center and

Vice-Chair of Ophthalmology, UCLA

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.

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.

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 2019 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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