Send Comments to IFOND

International Foundation for Optic Nerve Disease

Funding research and disseminating information on causes, prevention and treatment.
Welcome | Impact | Glaucoma | LHON | Toxic | Ischaemic | Projects | Donors | Coping | Glossary | Links | Use | About | Contact | Donate
IFOND Dictionary: Index | A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | NUM

IFOND research | LHON treatment prospects | Mitochondrial Genome Editing | COVID-19 and LHON | LHON talks | Pay it forward | Mitochondrial Regulation | Avoid BAK eye drop preservative, etc. | We experiment with cigarette smoke so you need not. | Viral vector trials | EPI-743 LHON trials | Idebenone LHON trials

Digests: NEI News | Mitochondrial Disease News LHON | ARVO Journals LHON | PubMed LHON | Europe PMC LHON | MRC-MBU news
Project updates: 2022 | 2019 | 2018 | 2017 | 2016 | 2015 | 2013 | 2011 | 2009 | 2008 | 2007 | 2006 | 2005-2001 |

Update for Brazil LHON Project with Special Emphasis on Brazil IX (2009)

Alfredo A. Sadun, MD, PhD

I was fortunate to again lead our international team of investigators to rural Brazil for our latest field investigation October 14-19, 2009. This, our ninth trip, was to the same remote area in Brazil allowed us to continue the examination of the world’s largest pedigree with Leber’s Hereditary Optic Neuropathy (LHON). My prior reports described the four main issues we initially 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 whether there was an increased risk of converting from carrier to affected status with diet, toxins and exposure to smoking, drinking and non-tobacco smoke. 3) Clinical characteristics of this giant pedigree with LHON: We brought to rural Colatina several neuro-ophthalmologists and, using sophisticated equipment, performed comprehensive neuro-ophthalmological examinations. 4) Psychophysical testing: We developed and employed novel testing, including cutting-edge psychophysical evaluation techniques such as multifocal ERGs. The developers of this technology participated in this visit. We also investigated a number of new serological measures of oxidative stress. Several conclusions were reached and published. These included the likelihood that both genetic and epigenetic factors effect conversion from carrier to affected status. Genetically, nuclear modifying genes influenced the penetrance rate of those affected. Environmental factors, including smoking and the consumption of alcohol, more than double the risk of going blind. This led to the conclusion that there are subclinical manifestations of the disease that could be commonly described in carriers. Further, we could observe chronic progression in non-affected carriers. For example, we found alterations in mfERG, color vision and contrast sensitivity in psychophysical testing. We also noted retinal nerve fiber layer swelling that could be documented photographically or by GDx and that was reflected in subtle visual field changes. The disease is more insidious, chronic and complicated than once thought.

Our published results are now widely accepted. The thinking is that a mutation of the11778 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 pores (MPTP) that liberates cytochrome C and this induces apoptotic death of the retinal ganglion cells. This occurs as a wave of death and optic atrophy, often triggered by environmental exposure to ROS (such as in smoke).

Brazil IV-VII also provided new insights that we have published. We described four patients who were without visual complaint and therefore unaffected. They all demonstrated subclinical changes that showed progression until they led to conversion into an affected status of blindness. We also made arrangements for specialized necropsy of eye, brain and peripheral nerve tissues for some members of the family who may die during the next few years. We brought and added a new technology in the form of Optical Coherence Tomography (OCT) that offered the clinical quantification of retinal nerve fiber thickening and losses. Color vision and contrast sensitivity testing was done with Cambridge Colour Systems. Fundus examinations consistently showed subtle findings. Repeat ERGs, Visual Fields (Humphrey) and GDx were performed. We also continue the OCT studies that are quite interesting in that they provide objective and quantifiable corroborations of the fundus examinations that some carriers were developing swelling of their retinal nerve fiber layers. Fundus photography rounded out the follow-up examinations. We performed blood testing for neuron specific enolase (NSE) and phosphorylated axonal heavy chain neurofilament (PAN), which has shown a dramatic elevation in LHON affected and in carriers. Most remarkably, in carriers this correlates very closely with the many clinical and psychophysical changes we have been measuring. In short, we have found at least one and probably two excellent biomarkers of this disease that can be used for any future clinical study of a therapeutic agent. Most recently, in 2009, we obtained serum samples from 60 patients that are being analyzed not only for NSE and PAN, but for about 150 other subtle parameters of the blood that measure oxidative stress. This will provide a baseline against which comparisons can be made for a new treatment we are considering. These publications have revolutionized the field providing a means of measuring proposed treatments for LHON.

Hence, we are at the cusp of the development of a treatment that hopefully will preclude or mitigate further visual loss in carriers with LHON. We have been working, in conjunction with collaborators, on a class of new molecules that have the properties of scavenging the high levels of free radical and which can be transported into mitochondria in high concentrations. These molecules have been developed largely by a group at Stanford and Edison Pharmaceuticals, of San Jose, California and they have tested well in cybrid studies performed in conjunction with Dr. Valerio Carelli in Italy., The newest version, called 743, has already been used twice in patients (as a compassionate use dispensation by the FDA) with a more horrible version of LHON that also causes brain degeneration in very young children called Leigh’s Syndrome. Although it has only been 6 weeks, both kids have shown some response to the medication and are doing better in a disease that usually goes downhill very fast. We have a preparation of 743 that is topical and can be applied to the eye without any systemic side effects. I am scheduled to go to Washington DC and testify for the FDA at the NIH in about 2 months to ask permission to use this in a few selected cases of LHON. We will then do this at Doheny, in LA to make sure we can monitor the use of the drug very carefully. Afterwards, assuming at least a safe profile of effects, we will take this to Brazil for a larger clinical trial (hopefully, October 2010).

We will try and apply the new drug first to affected to ensure no ill effects and then to carriers in the hope of not only improving the serum markers, but the many subclinical measures that we’ve been making in them for almost ten years. We are hopeful that this medication will prove effective at least in preventing carriers from converting and going blind. We may even be so lucky as to see some modest improvement in the vision of LHON patients who have already lost their sight.

Respectfully submitted,

Alfredo A. Sadun, MD, PhD

November 5, 2009

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
Welcome | Impact | Glaucoma | LHON | Toxic | Ischaemic | Projects | Donors | Coping | Glossary | Links | Use | About | Contact | Donate

Donate to IFOND sponsored research. You can designate which area of current IFOND activities to direct your funds:
>> Donate online <<
donate directly to IFOND at the address below:

The International Foundation for Optic Nerve Disease
P. O. Box 777, Cornwall NY 12518, USA.
Phone/Fax: (845)5348606
Web site:

IFOND is registered service mark of The International Foundation for Optic Nerve Disease, est. October 1995.

Copyright 1999-2023, 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.