Discovering Novel Autophagy Activators

Background

Ageing is associated with the decline in the capacity of the autophagy pathway to degrade dysfunctional and damaging cellular components, such as protein aggregates and mitochondria. Dysfunctional autophagy, in turn, undermines other cellular functions including DNA repair, metabolism and survival. Therefore, activation of autophagy is considered a promising therapeutic approach to combat ageing and age-related diseases.

Aims, Hypothesis & Results

Lysosomal dysfunction is an important factor contributing to the reduction of autophagy during aging. As dysfunctional lysosomes interfere with autophagy at the terminal stage, stimulation of autophagy initiation can be ineffective to rescue autophagy. Additionally, current methods to measure autophagy are rather unreliable, slow, and with complicated readouts, making the screening of compounds that promote autophagy less efficient. To model lysosomal dysfunction, Prof. Korolchuk lab uses cells with a mutation in a lysosomal protein (Npc1) associated with neurodegenerative diseases. When these cells are subjected to metabolic stress, they suffer cell death due to dysfunctional autophagy, providing an easy readout for an autophagy assay (cells dead/cells alive). To identify true autophagy activators, Prof. Korolchuk lab uses cells that lack initiation of autophagy and are therefore not rescuable by autophagy inducers in parallel with Npc1 KO cells.

Korolchuck lab proposes to initiate a drug discovery programme with the aim of identifying novel bioactive autophagy inducers.

Timeline

Pre-Clinical Studies 1: Identification of Lead Compounds
Required Funding: $85,000
Status: Ongoing
Duration: 12 Months
Pre-Clinical Studies 2: Synthesis and Testing
Required Funding: $20,000
Status: Planned
Duration: 2 Months
Pre-Clinical Studies 3: Future Work Upon Lead Identification
Required Funding: $30,000
Status: Planned
Duration: 6 Months

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VitaDAO Board Evaluation Writeup

All of the VitaDAO evaluators considered this project worthy of funding. The assay has an easy readout, decent throughput, good controls and targeting one of the most important processes in cellular aging (autophagy). Proof-of-principle was already in place as Korolchuk Lab had previously identified hits with this approach by screening an FDA-approved compound library. The screening platform would also allow collaboration with other projects targeting autophagy/mitophagy and has potential for generation of IP/NFT for compounds. Risks to consider are the necessity for the screen to provide hits and that the specific knockout model they are using translates to having general relevance in ageing. However, the team is working on addressing the latter risk, with promising data suggesting this might not be a problem.