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5. Research reports of scientific board members:

• Alfredo: Two parallel approaches to studying LHON:
• Computational chemistry of the G3460A mutation of ND1 (the most severe form of LHON):
to determine the structure of the normal and mutated ND1, and how this mutation affects the transfer of electrons from ND1 to ubiquinone. They found that the substitution of amino acids alanine to threonine at position 52 “leads to an additional -OH right in the path of the moving ubiquinol”. Consequently, it “creates electrostatic forces that ultimately block movement of ubiquinol and generates ROS” (reactive oxygen species), which are detrimental to “retinal ganglion cells, their fibers in the optic nerve and ultimately cause blindness in LHON” (quotations are from Alfredo’s working manuscript). See also Alfredo’s Progress Report
• Using cybrids from Valerio and UCLA, they found that the rate of mutation of ND1 changes with temperature. The conversion of alanine to threonine at position 52 may be associated with electrostatic attraction and electron tunneling, requiring extra energy to overcome it.

• Valerio:
• He will be organizing an International meeting in Bologna in June of 2023 on mitochondrial diseases. He said that it may be good to have a LHON meeting attached to it. Fred indicated that IFOND may consider raising funds to support the LHON meeting. He asked if Valerio and Chiara can submit written outlines of their current research activities to the Board for consideration.
• His paper on mitophagy (which utilized electron microscopy in Los Angeles) submitted to Cell Reports is undergoing a second round of revision, which requires 6 months to do the experiments. When complete, he will share the paper with the Board.
• He is undertaking whole genome sequencing of 20 Brazilian family members: both affected individuals and unaffected carriers.

• Rustum:
• He will be submitting a proposal to RDMM for possible co-funding by IFOND as described above.
• His AI (artificial intelligence) project is finally underway, as Ottawa is getting an OCTA (optical coherence tomography angiography). He will analyze the AI data and determine if those from Canada (his) and UK (Patrick’s) correspond with those from the US and Italy, the latter groups being obtained from trained medical personnel (i.e., not AI). This will help to determine if the model is correct.

• Patrick:
• Benson Chen, MD, is formally accepted as a PhD student by the University of Cambridge.
• Benson has developed a patient-reported outcome measure (PROM) questionnaire for patients with inherited optic neuropathies. Stage One has been completed, resulting in a publication and another one in press. Stage Two involves Zoom Pro with about 20 participants with LHON or ADOA (autosomal dominant optic atrophy). The transcribed interviews will be analyzed with a software package (NVivo 12). The final phase will be in a year.
• Benson is also involved with a project to standardize nomenclature used for LHON. This project was spearheaded by Rustum and Lissa (Poincenot).
• Please see Patrick’s Progress Report.

6. Possible IFOND-funded meetings:
• Fred raised the possibility of IFOND funding a 1-2 day meeting in association with established national or international meetings (such as ARVO, NANOS, etc.). The Board can come up with a list of guest speakers. Alfredo mentioned that such has been done in the past in conjunction with ARVO. The 2023 meeting in Italy organized by Valerio will be a good venue, and it would be good to invite Solange from Brazil to speak.

7. Brazil 2022?
• Rustum indicated that it will not be feasible to go to Brazil in 2022 due to COVID.

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