Niemann-Pick disease type C (NPC) is a rare, inherited metabolic disorder that impairs the body’s ability to properly process cholesterol and other fats (lipids). This causes these substances to accumulate to harmful levels within cells. The buildup primarily affects organs like the brain, spleen, and liver, leading to a progressive decline in function.
The Cellular Basis of Niemann-Pick Type C
Niemann-Pick type C originates from mutations in one of two genes: NPC1 or NPC2. In approximately 95% of cases, the mutation occurs in the NPC1 gene. These genes provide instructions for producing proteins that help move cholesterol and other lipids out of the lysosome.
The lysosome is the cell’s recycling and waste disposal center. The NPC1 and NPC2 proteins work to move fats out of the lysosome for use elsewhere in the cell. When a mutation occurs in either gene, the resulting protein is defective or absent, causing this transport system to fail.
This failure creates a “traffic jam” of cholesterol and other lipids inside the lysosomes. This accumulation is toxic, leading to cell damage and death. This cellular damage causes the disease’s wide-ranging symptoms, including the severe neurological deterioration that characterizes NPC.
Current Therapeutic Approaches
In September 2024, the U.S. Food and Drug Administration (FDA) approved two medications for NPC. The first, Miplyffa (arimoclomol), was approved for adults and children aged two years and older. Arimoclomol amplifies the activity of “heat shock proteins,” which help stabilize the defective NPC1 protein, improve lysosome function, and protect against cell death.
Arimoclomol is approved for use in combination with miglustat. Miglustat, previously available off-label in the U.S., has been used in other regions for some time. It functions as a substrate reduction therapy, slowing the rate at which cells produce complex fats called glycosphingolipids. This reduces the amount of material sent to the lysosomes, lessening the storage burden on the compromised system.
Shortly after arimoclomol’s approval, the FDA also authorized Aqneursa (N-acetyl-L-leucine) to address neurological symptoms in adult and pediatric patients. Its effectiveness was measured by improvements in ataxia, which includes issues with gait, stance, and speech. Patients treated with Aqneursa showed better outcomes in these areas compared to a placebo. Both arimoclomol and Aqneursa are oral medications.
Another compound, hydroxypropyl-beta-cyclodextrin (HP-β-CD), is available through clinical trials or compassionate use programs. It acts like a molecular “sponge,” binding to trapped cholesterol inside cells. This forms a complex that is more easily cleared from the lysosome, removing the toxic buildup. To be effective for neurological symptoms, it often requires direct administration into the cerebrospinal fluid to bypass the blood-brain barrier.
Investigational Drugs and Clinical Trials
Research continues to explore new therapeutic avenues for Niemann-Pick type C. Scientists are pursuing multiple strategies aimed at addressing the root cause of the disease and its downstream effects.
One of the most advanced areas of research is gene therapy. The goal is to introduce a correct copy of the mutated NPC1 or NPC2 gene into a patient’s cells. This approach seeks to restore the production of functional NPC proteins, thereby correcting the underlying defect in lipid transport.
Other therapeutic candidates are also being investigated. For instance, histone deacetylase inhibitors, such as Vorinostat, have shown an ability to prevent lipid accumulation in cellular models of the disease. These ongoing studies are important for discovering more effective treatments and improving outcomes for individuals with NPC.
Supportive and Symptomatic Management
Beyond medications that target the disease’s cellular mechanisms, a plan for managing symptoms is necessary to improve a patient’s quality of life. This care often involves a multidisciplinary team of healthcare professionals who work together to provide holistic support.
Physical therapy helps patients maintain mobility, balance, and muscle strength. Occupational therapists assist with adapting daily living activities, such as dressing and eating, to accommodate physical limitations and help individuals retain independence.
Difficulties with swallowing (dysphagia) and communication are common neurological symptoms. Speech-language therapists provide strategies and exercises to manage these issues safely and effectively. Physicians may also prescribe medications to control specific symptoms like seizures, muscle stiffness (spasticity), or psychiatric disturbances.