Targeting NAD+ biosynthesis and excitotoxicity: two universal strategies for the treatment of amyotrophic lateral sclerosis

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with rapid disease progression. Patients suffer from muscle weakness and paralysis which usually result in death three to five years after disease onset. Although much is known about the disease pathogenesis, up to date, no treatment options exist to stop disease progression. However, there is ample evidence that disturbed energy metabolism and excitotoxicity majorly contribute to disease pathogenesis. Considering the urgent need for effective causal therapies to medicate ALS patients, it is of particular interest to identify new strategies to prevent neuronal loss and to slow or even stop disease progression. Ongoing studies using novel approaches, such as antisense oligonucleotides (ASOs) or viral gene therapy mainly focus on familial ALS forms, i.e. patients harboring SOD or C9ORF72 mutations. However, the vast majority of patients suffer from the sporadic form not associated with particular inherited gene modifications. The primary goal of this proposal is the evaluation of universal targets for the treatment of sporadic ALS by developing and pre-clinically testing promising treatment strategies for rapid translation into the clinic. This is also the central maxim of the Center for Translational Neurodegeneration Research at the University of Texas Southwestern Medical Center which will host this project.Here, I present two concepts targeting two universal pathways involved in the pathogenesis of ALS: dysfunctional NAD+ biosynthesis and excitotoxicity, respectively. First, based on a recent clinical study indicating that increasing NAD+ levels has disease-modifying properties in ALS patients, we hypothesize that enhancing NAD+ metabolism can delay disease progression in ALS animal models. To test this, I will increase the expression of nicotinamide phosphoribosyl transferase (NAMPT), a key rate-limiting enzyme for NAD+ biosynthesis, using adeno-associated viral vector gene delivery. The second strategy builds on the observation that suppression of calcium (Ca2+)-activated phospholipid scramblase 1 (PLSCR1) activity (i.e. excitotoxicity-activated) prevents microglial activation and intracellular Ca2+ dysregulation. Therefore, I aim to investigate the effect of ASO-mediated PLSCR1 inhibition on excitotoxicity-related motor neuron cell death and disease progression in pre-clinical ALS models. If proving effective, the tested strategies can be directly employed in the clinic and are expected to be beneficial for a wide spectrum of ALS patients.