NAD+-Biosynthese und Exzitotoxizität: zwei universelle Angriffspunkte für die Behandlung der amyotrophen Lateralsklerose
Zusammenfassung der Projektergebnisse
In this project, we sought to investigate a gene therapy approach for the treatment of neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), by targeting dysregulated energy homeostasis. One key molecule in the cell essential for energy metabolism is nicotinamide adenine dinucleotide (NAD+), which is known to be reduced in neurodegenerative conditions. Our strategy was based on increasing NAD+ levels by boosting the expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ production. I successfully produced a viral vector for the adeno-associated virus (AAV)-mediated delivery of human codon-optimized NAMPT (hNAMPTopt). Injection into the central nervous system resulted in robust hNAMPTopt expression predominantly in the brain. To test the effect of AAV- hNAMPTopt treatment in the context of ALS, we used a Vps54-mutant mouse model (wobbler mouse), which develops motor symptoms starting at the age of three weeks. Neonatal mouse pups were intracerebroventricularly injected with AAV-hNAMPTopt and monitored for symptoms and changes in body weight for 50 days. AAV-hNAMPTopt treatment did not alter the time of disease onset, disease progression, or severity at the end of the observation period compared to naïve wobbler mice. We conclude that boosting NAMPT levels in this mouse model via AAV-mediated gene therapy is not sufficient to protect from neurodegeneration. Nevertheless, NAD+ metabolism remains a promising target to universally prevent neurodegeneration and it is worthwhile to further investigate approaches to maintain physiological neuronal energy homeostasis as a therapeutic strategy.
Projektbezogene Publikationen (Auswahl)
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"Lipoprotein receptors." Biochemistry of Lipids, Lipoproteins and Membranes. Elsevier, 2021. 583-622
Kuhbandner, Kristina, Joachim Herz, and Theresa Pohlkamp
