01 Jan
NR as a Promising Therapeutic Candidate for Alpers' Disease
Introduction
Alpers' disease is both a neurodegenerative disorder and a metabolic disorder, which is tightly linked to mitochondrial dysfunction and mutations in the catalytic subunit of polymerase gamma (POLG) gene. Noteworthily, supplementation of NAD precursor, nicotinamide riboside (NR), is evidenced to explicitly ameliorate mitochondrial defects in cortical organoids of patients with Alpers' disease.
About Alpers’ disease
Alpers’ disease is an autosomal recessive disorder, which is often accompanied with cortical neuronal loss as well as depletion of mitochondrial DNA (mtDNA) and complex I (CI). The disease occurs in about 1 in 100,000 newborns. Most individuals with Alpers’ disease show no symptoms at birth. Diagnosis is generally established by determining the POLG gene. Once onset (usually between first and third years of life), patients may present the symptoms such as progressive encephalopathy, epilepsy, myoclonus, and myasthenia gravis. Currently, there is no effective method to cure this disease.
Establishment of Alpers' disease model in vitro
Induced pluripotent stem cells (iPSCs) are generated from Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), followed by differentiation into cortical organoids and neural stem cells (NSCs). Alpers's iPSCs exhibit mild mitochondrial alterations, including an elevated L-lactate level and a depletion of CI. Alpers' NSCs manifest profound mtDNA depletion and mitochondrial dysfunction. Alpers' cortical organoids demonstrate cortical neuronal loss and astrocyte accumulation.
The role of NR in Alpers' cortical organoids
Long-term treatment with NR partially ameliorates the neurodegenerative alterations observed in Alpers' cortical organoids. Specifically, supplementation of NR effectively counteracts neuronal loss, glial enrichment, and mitochondrial damage observed in cortical organoids of patients with Alpers' disease.
Reversal of the dysregulated pathways in Alpers' patient organoids post NR treatment
NR treatment offsets the downregulation of mitochondrial and synaptogenesis-related pathways, as well as upregulation of pathways associated with astrocyte/glial cells and neuroinflammation are obviously activated in Alpers' cortical organoids.
Conclusion
Replenishment of NR to increase NAD level can rescue mitochondrial defects and neuronal loss in iPSC-derived cortical organoid of Alpers’ disease, with relatively high safety and bioavailability, showing great promise as a therapeutic candidate for this intractable disorder.
Reference
Hong Y, Zhang Z, Yangzom T, et al. The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease. Int J Biol Sci. 2024;20(4):1194-1217. Published 2024 Jan 25. doi:10.7150/ijbs.91624
BONTAC NR
BONTAC is one of the few suppliers in China that can launch mass production of raw materials for NR, with self-owned factory and professional R&D team. Up till now, there are 173 BONTAC patents. BONTAC provides one-stop service for customized products. Both malate and chloride salt forms of NR are available. By dirt of unique Bonpure seven-step purification technology and Bonzyme Whole-enzymatic method, the product content and conversion rate can be maintained in a higher level. The purity of BONTAC NR can reach above 97%. Our products are subjected to strict third-party self-inspection, which are worth of trustworthy.
Disclaimer
This article is based on the reference in the academic journal. The relevant information is provided for sharing and learning purposes only, and does not represent any medical advice purposes. If there is any infringement, please contact the author for deletion. The opinions expressed in this article do not represent the position of BONTAC.
Under no circumstances will BONTAC be held responsible or liable in any way for any claims, damages, losses, expenses, costs or liabilities whatsoever (including, without limitation, any direct or indirect damages for loss of profits, business interruption or loss of information) resulting or arising directly or indirectly from your reliance on the information and material on this website.
Under no circumstances will BONTAC be held responsible or liable in any way for any claims, damages, losses, expenses, costs or liabilities whatsoever (including, without limitation, any direct or indirect damages for loss of profits, business interruption or loss of information) resulting or arising directly or indirectly from your reliance on the information and material on this website.