Most cells generate most of their energy using mitochondria. Mitochondria are organelles that specialize in producing ATP by oxidative phosphorylation (OXPHOS). The most prominent diseases after the age of 65 years are linked to organs and tissues with the highest energy demand on their mitochondria – the brain and the heart. These diseased organs also age prematurely according to the epigenetic aging clock.

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Mitochondria retain their own genome encoding proteins critical for energy production. Unlike the nuclear genome, which contains two copies of each gene (with certain exceptions), the mitochondria contain hundreds to thousands of gene copies. With age, the mitochondrial genome number decreases and surviving genomes suffer damage.

The most robust strategy to increase energy production from mitochondria is to repair age-accumulated damage to the mitochondrial genome. Gene editing provides one approach, but is designed for repair at specific genome locations (age-accumulated damage occurs at diverse genome locations). Gene editing also carries significant clinical risk because it relies on unproven systemic gene therapy.

We have identified small molecule ‘Shift’ drugs that combat diverse age-accumulated mitochondrial genome damage and do not rely on systemic gene therapy.

It has been known for > 25 years that under certain conditions, the cell can reduce the proportion of damaged mitochondrial genomes (Tonsgard & Getz 1990, Dunbar & Holt 1995, Manfredi & Schon 1999), a phenomenon known as the ‘Shift’ effect. The mechanism was never uncovered and these experimental observations faded into obscurity.

During his PhD project at the MRC Laboratory of Molecular Biology at the University of Cambridge, Dr Daniel Ives harnessed bioinformatic databases and analytic tools to identify small molecule compounds (Shift drugs) that trigger the Shift effect in cells from individuals with the orphan disease MELAS. He demonstrated that these could increase oxygen consumption in MELAS cells from ~5% to 100% the level of age matched healthy individuals.

Our subsequent research into the underlying mechanism of this effect suggests that Shift drugs act by increasing competition between mitochondria for scarce resources. Mitochondria import the majority of their proteins. When this protein supply is constrained, undamaged mitochondria are able to out-compete the damaged mitochondria and this gives them a replicative advantage.

SB002 is a molecule discovered by Shift Bioscience to be particularly effective in promoting this greater level of mitochondrial competition inside the cell. We have demonstrated that SB002 can be used to trigger the Shift effect in cells containing damaged mitochondria sourced from an individual with Parkinson’s disease, resulting in an increase in oxygen consumption.

Mice engineered to elevate the rate of damage accumulation in their mitochondrial genomes (POLG mice) exhibit accelerated aging. Recently we have demonstrated that SB002 can slow the progression of visible signs of aging in POLG mice. During treatment with the drug, internal aging markers (heart hypertrophy, elevated glucose) are reduced.

We will minimize costs and timescales for clinical development of Shift drugs by first targeting the orphan disease MELAS, which is caused by inherited mitochondrial dysfunction. A clinical trial for MELAS requires fewer participants due to the rarity of the disease and the larger degree of unmet clinical need. Drug efficacy is easier to demonstrate due to clearer biological/clinical endpoints.

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