Major Theme: Neuronal NAD+ metabolism

We have previously discovered metabolic dysfunction and mitochondrial abnormalities occurring prior to neurodegeneration in glaucoma (in glaucoma patients and glaucoma animal models). These studies identified that the capacity to maintain NAD pools declines in the retina in an age-dependent manner and renders retinal ganglion cells susceptible to IOP-related stress, driving glaucomatous neurodegeneration (Williams et al., Science, 2017). Preventing NAD depletion via administration of nicotinamide (NAM; the amide of vitamin B3; an NAD precursor) or through gene therapy (NMNAT1 or NMNAT2; terminal enzymes for NAD production) robustly protects from age-related neuronal metabolic decline and prevents glaucoma in animal models (Williams et al., Science, 2017, Tribble, Jöe et al., Nature Comms, 2024). Supporting a hypothesis in which pathogenically low NAD leads to glaucoma susceptibility, glaucoma patients have been demonstrated to have systemically low levels of nicotinamide (in sera), low NAD correlates with glaucomatous progression (Petriti et al., Nature Medicine, 2024), and, as part of an international collaborative clinical trial, we have demonstrated that elevating NAD levels through NAM administration can improve visual function in existing glaucoma patients (Hui et al., CEO, 2020). This is the first example of a successful glaucoma clinical trial that does not target IOP lowering, strongly supporting the case for raising NAD in glaucoma, exemplifying my commitment to developing novel treatments for glaucoma. Importantly, we were able to translate a finding from mouse-to-man in just three years. Pete is now part of the leadership team in the Phase III multicentre clinical trial testing NAM in new, mild, and moderately advanced glaucoma patients (1800 patients across Australia, Singapore, Sweden, and the UK: The Glaucoma Nicotinamide Trial; TGNT, NCT05275738).

Although this is clinically promising, NAM is required at high doses, is not neuron-specific, and has numerous off target effects (e.g. regulation of vascular tone). To address this, we have targeted the upstream enzyme in axon degeneration, NMNAT2, to provide a neuron-specific neuroprotection. Targeting NMNAT2 is challenging and NMNAT2 is yet to be successfully drugged, with most researchers and companies focusing instead on inhibition of a downstream effector molecule: SARM1. However, SARM1 is not neuron specific and doesn't replete pools of NAD once these pools are depleted. We have improved on this through a series of in silico and neurobiological tests to identify a critical binding pocket on NMNAT2 which we have successfully pharmacologically targeted to increase NAD pools in a neuron specific manner (using genetic and pharmacological methods to test specificity in vitro and in vivo) (Tribble, Jöe et al., Nature Comms, 2024). Using these data we initiated an iterative design-synthesis-evaluation process generating of >120 novel compounds that drive NAD in an NMNAT2 and NMN specific manner. This is a major focus of our current work and that of our spin-out start-up company Mim Neurosciences AB.