Alpers Disease: New Avenues for Treatment Through Groundbreaking Research

Its onset in childhood and the severe impact on patients’ lives make understanding and combating this disease a high priority even relative to its rarity.

The mitochondria play a central role mostly affected by genetic mutations of the POLG gene. This gene is vital for replication and repair of mitochondrial DNA, which in the case of mutation portrays a cascade of symptoms affecting different body systems. Only in the last few years have specific areas of research, especially those with induced pluripotent stem cells (iPSCs) from patients with Alpers disease, identified and suggested the possible therapeutic role for NAD+ supplementation in said disease.

The pathogenesis of Alpers disease, highlights  the innovative use of nicotinamide riboside (NR) in mitigating mitochondrial defects and opening new paths for treatment strategies.

Understanding Alpers Disease

Alpers disease is an inherited condition that manifests as a severe neurodegenerative disorder, often beginning in early childhood. Symptoms are varied but typically include progressive loss of cognitive and motor skills, seizures, and liver dysfunction, leading to a significantly reduced life expectancy. The root of this disease lies in the POLG gene, responsible for producing an enzyme essential for mitochondrial DNA maintenance. Mutations in the POLG gene disrupt normal mitochondrial function, leading to cellular energy deficits and, ultimately, the symptoms observed in Alpers disease.

The Significance of Mitochondrial Dysfunction

Mitochondria, often referred to as the powerhouse of the cell, play a vital role in energy production and cellular health. Beyond energy, they are involved in regulating cell death and maintaining the cell’s balance of calcium ions, among other critical functions. Mitochondrial dysfunction, therefore, has far-reaching implications, affecting the nervous system, muscles, and various organs. In the context of Alpers disease, compromised mitochondrial DNA replication and repair capacity lead to neuronal loss and severe developmental issues, underscoring the importance of maintaining mitochondrial health.

Recent studies have unveiled a critical link between NAD+ levels and mitochondrial health in the context of Alpers disease. In patient-derived neural stem cells (NSCs) and cortical organoids, which are simplified, miniaturized versions of the brain grown in vitro, NAD+ levels were found to be significantly depleted. This depletion coincides with mitochondrial dysfunction, characterized by abnormal mitochondrial structure, reduced membrane potential, increased production of reactive oxygen species (ROS), and lowered ATP levels—hallmarks of Alpers disease.

Remarkably, treatment with Nicotinamide Riboside (NR), a precursor to NAD+, showed promising results. Administered over two months, NR was able to alleviate many of the mitochondrial-related abnormalities in the patient-derived cortical organoids. These findings suggest that NR supplementation could have neuroprotective effects, potentially halting or even reversing some of the damage caused by mitochondrial dysfunction in Alpers disease.