For years, researchers have been evaluating pridopidine, developed by Prilenia Therapeutics (“Prilenia”), as a potential therapy for patients with neurodegenerative conditions. As reported in HD Buzz, new research has highlighted pridopidine’s underlying mechanisms. As a result, scientists understand how the treatment works and have reaffirmed the belief that it could be a safe and effective treatment option for Huntington’s disease (HD).

Interested in learning more? Check out this article published in the Journal of Neurochemistry. You may also look at this article in Neurotherapeutics or this article within the International Journal of Molecular Sciences. Findings will be shared below.

Pridopidine

Initially, researchers believed that pridopidine could regulate dopamine in the brain, as dopamine plays a role in movement. Altogether, researchers evaluated this within the MermaiHD, PRIDE-HD, and HART clinical trials. Although the trials showed that the drug was relatively safe and well-tolerated, it showed little improvement on motor function. Additionally, the drug failed to slow HD progression.

At the same time, patients taking pridopidine better managed daily tasks, as measured by Total Functional Capacity (TFC). Currently, the Phase 3 PROOF-HD clinical trial is recruiting patients. Altogether, 480 patients will enroll and the trial will run until 2023. During this time, researchers seek to understand whether the treatment actually improves TFC.

New Research

Although clinical trials have been occurring, researchers within the lab have also been looking to understand exactly how pridopidine works. What are the drug’s underlying mechanisms? How exactly could it work to improve symptoms and QOL? Conclusively, researchers determined that the drug does affect dopamine. That being said, it more strongly impacts and targets the sigma-1 receptor (S1R). According to Prilenia:

Activation of the S1R by pridopidine enhances the clearance of toxic proteins, enhances energy production, and reduces cellular stress and inflammation. These mechanisms are crucial for a neuron’s function and survival.

Within the first publication, researchers evaluated pridopidine in mice models of HD and patient nerve cells. The research found that treated mice models saw improved mitochondrial function, relieving cellular stress. Human nerve cells responded in a similar fashion. Thus, pridopidine could help restore mitochondrial function through targeting and activating S1R.

In the second publication, researchers sought to understand whether pridopidine relieved nerve cell stress within the endoplasmic reticulum (ER). In patients with HD, the ER is overstressed and functions poorly. Researchers determined that pridopidine reduced ER stress and improved function. However, these findings were not replicated if cells were missing S1R, suggesting S1R enhances pridopidine function.

Finally, the third study shows that S1R sometimes associates with cholesterol, but this is interrupted by pridopidine. Ultimately, this improves ER function.

Because the research shows that the drug reduces cellular stress, it does offer an opportunity to treat patients with HD and reduce symptoms. However, whether this can be replicated in a clinical trial has yet to be seen.

Huntington’s Disease (HD)

HTT gene mutations cause Huntington’s disease (HD), a neurodegenerative disease that causes the progressive breakdown of nerve cells in the brain. Normally, HTT tells the body how to create huntingtin, which plays a role in neuronal function. In HD, HTT mutations cause long, toxic huntingtin chains, which break down, bind to neurons, and cause neuronal death. In most cases, HD impacts those of European ancestry. An estimated 3-7 in every 100,000 people will develop HD.

Juvenile HD is rare and usually appears in adolescence. An estimated 30-50% of patients with this condition experience seizures. Additionally, the lifespan is shorter – around 10-15 years following diagnosis. Alternately, adult-onset HD is the more common (but still rare) form. Typically, patients are diagnosed within their 30s or 40s. Following diagnosis, the average lifespan is around 15-20 years.

Symptoms include:

• Chorea (uncontrolled jerking or twitching movements)
• Anxiety and/or depression
• Irritability
• Difficulty learning or retaining new information
• Forgetfulness
• Poor decision-making
• Mood swings, impulsivity, and other changes in behavior and personality
• Difficulty walking, speaking, or swallowing
• Learning difficulties
• Muscle rigidity
• Drooling
• Poor coordination