Send Comments to IFOND

International Foundation for Optic Nerve Disease
P. O. Box 777, Cornwall NY 12518, USA

Email: IFOND@aol.com
Phone [g voice]: 6572067250

 
Please DONATE to IFOND once or regularly to the address above, or click here to JustGive.org.

Update for Brazil LHON Project with Special Emphasis on Brazil XI (2011)

Alfredo A. Sadun, MD, PhD


Finally! After ten years of leading our international team to Brazil every year, and in debt to the hundreds of patients with the Leber's Hereditary Optic Neuropathy (LHON) gene who turn up to spend days with us in repeat examinations, we finally brought this extended family a new treatment option.


This year our international team of investigators, led by Drs Sadun and Carelli, brought a new pharmaceutical agent to try in our annual field investigation to rural Brazil: October 13-19, 2011. This was the culmination of a lot of clinical and basic science research. But it was also the conclusion of negotiations with various relevant authorities and organizations. We are grateful to all parties and especially to IFOND and Edison Pharmaceuticals that helped support these expenses.


We conducted our annual trip to the same remote area in Brazil with the fundamental mission being to continue the investigation of the world's largest pedigree with LHON. In my prior reports, I detailed four main issues that we addressed: 1) Genetics: We found, organized and defined the world's largest pedigree of LHON established to be 11778, homoplasmic, J-haplogroup. 2) Epigenetics and epidemiology: We investigated and were the first to report an increased risk of converting from carrier to affected status with exposure to drinking, smoking, and even non-tobacco smoke. 3) The clinical characteristics of LHON were described in this giant pedigree: We brought to rural Colatina several neuro-ophthalmologists and, using sophisticated equipment, performed comprehensive neuro-ophthalmological examinations. By this prospective comprehensive process, we were the first to characterize the natural history of the disease from before conversion to affected status. 4) Psychophysical testing and biomarkers: We developed and employed novel testing, including cutting-edge psychophysical evaluation techniques. We also investigated a number of new serological measures of oxidative stress.


We reached many conclusions and published over 24 peer-reviewed articles as well as nearly one hundred abstracts and presentations. These described that both genetic (nuclear modifying factors) and environmental factors effect conversion from carrier to affected status. For example, smoking and the excessive consumption of alcohol more than double the risk of going blind in those that carry the LHON mutation. We also found that there are subclinical manifestations of the disease that could be commonly described in carriers. We described abnormalities in color vision and contrast sensitivity. We noted swellings at points along the optic nerve head and corresponding retinal nerve fiber layer (NFL) swelling that could be measured by optical coherence tomography (OCT). LHON is more insidious, chronic and complicated than once thought.


We were the first to describe OCT findings in LHON. This year we added the newer generation Cirrus instrument to our armamentarium. About 20% of women and over 80% of male unaffected carriers have subtle OCT findings. With this instrument, we better documented the natural history of NFL swelling followed by NFL atrophy in the course of going from carrier, to conversion, and then to affected.


Having previously proven the preservation of the melanopsin retinal ganglion cells (mRGC) in LHON, we extended our pupillometry protocol with Ganzfeld. Pupillary constriction in blind (affected) LHON patients could be maintained with light that was specifically tuned (by wavelength, color, intensity and duration) for mRGCs. We hope to eventually control the stimulation of mRGCs even in blind LHON patients to exploit an alternate pathway for such patients to see.


All of this derives from the collaboration that we've had with Edison Pharmaceuticals working with on a new agent: alpha-tocotrienol-quinone (EPI-743). The mechanism of action is probably similar to Idebenone. This molecule should help shuttle electrons and reactive oxygen species (ROS) that accumulate as a product of Complex I dysfunction which is the problem in LHON. Initial experiments were first done with cybrids and demonstrated greater efficacy with EPI-743 than with Idebenone. Then we treated 12 patients of mine with LHON in Los Angeles. This was possible only through a compassionate use open label trial that the Food and Drug Administration (FDA) allowed. The FDA now requires us to move to a more formal prospective placebo controlled double blind study. But first, and in conjunction with Brazilian authorities, they will permit the treatment of the last four Brazilian LHON patients to lose vision. We begin now and will follow carefully and will know much more in one year. Dr. Felipe Chicani will return every two months to Brazil to work with Rubens Belfort at the Federal University of Sao Paulo.


The results of these 11 investigations to Brazil have transformed the textbooks on the subject of LHON. It is now understood and accepted that mutations such as to the 11778 gene, causes a defect of complex I that not only leads to a blockage of electron transport, but also to the production of reactive oxygen species (ROS). This changes the membrane potential of the mitochondria and induces an opening of the mitochondrial permeability transition pores (MPTP) that liberates cytochrome C, which in turn, at a critical threshold level, induces apoptotic death of the retinal ganglion cells. This occurs as a wave of cell death and optic atrophy and follows a sequence for which we have mathematical models and depends on large part on the caliber of the axons from the retinal ganglion cells.


Respectfully submitted,


Alfredo A. Sadun, MD, PhD

December 31, 2011

Doheny Eye Institute

If you find this site helpful or IFOND sponsored research worthwhile, please donate to IFOND at the address below, or JustGive.org.

The International Foundation for Optic Nerve Disease
P. O. Box 777, Cornwall NY 12518, USA.
Phone [g voice]: 6572067250
Email: ifond@aol.com
Web site: http://www.ifond.org/


IFOND is registered service mark of The International Foundation for Optic Nerve Disease

Copyright 1999-2017, International Foundation for Optic Nerve Disease.


The information contained on this website should not be considered medical guidance or professional advice. IFOND is not responsible for errors or omissions in information provided on this site or actions resulting from its use. IFOND does not publish all information from all available sources on optic nerve disease. IFOND is not responsible for the validity of the studies or reviews nor is it an advocate of studies or reviews mentioned on or linked from the IFOND web site. IFOND does not endorse or recommend participation in any particular clinical trial or treatment protocol which may be mentioned on this site. Direct any questions concerning your personal health to your appropriate health care professional.