Aducanumab: A new hope for Alzheimer’s disease treatment

While many other diseases take a person’s life, there’s also a few ones which gradually steal life away while a person is still technically alive & functioning, Alzheimer’s is one of the latter type. We all probably have seen the movie ‘The Notebook’, where we see how a dear one, suffering from Alzheimer’s disease becomes a total stranger. Even if we haven’t personally known an Alzheimer’s patient, we can imagine the pain & sufferings undergone by the patients & their families. According to a report sponsored by WHO in May 2018, Alzheimer’s is one of the leading causes of death, contributing to more deaths than cancer, diabetes, tuberculosis & road accidents.¹

 

As the most common form of dementia, Alzheimer’s disease is a neurodegenerative disease that is characterized by accumulation of extracellular amyloid beta plaques & intracellular neurofibrillary tangles. Recent studies support the idea that the accumulation of amyloid beta (Aβ) in brain is caused by an imbalance between the production and clearance of Aβ.² The most common symptoms of the disease are: memory loss, confusion, mood swings, disorientation and in severe cases death of brain cells & loss of brain activity leading to death.

 

Figure 1. A schematic of brain cells of a healthy patient (left) and one diagnosed with Alzheimer’s disease.³

 

Scientists have been looking for antibody-based immunotherapy against Aβ (Amyloid β) to enhance the clearance or reduce the neurotoxic effects of Aβ plaques. Aducanumab is a human monoclonal antibody that selectively targets Aβ plaques. Aducanumab can enter the brain by crossing the blood brain barrier. Once inside the brain, Aducanumab binds parenchymal Aβ, and reduces the extent of Aβ plaques. Aducanumab was developed using the human memory B cells. Human memory B cell is known to be active against the aggregation of β-amyloid. The methodology used involved screening the human memory B cells to identify antibodies that selectively binds the aggregated forms of β-amyloid.  The antibodies were then cloned and sequenced to develop the recombinant form, the drug Aducanumab.⁴

 

Aducanumab reduces brain Aβ plaques in a dose- and time-dependent manner in patients with prodromal or mild Alzheimer’s.⁴ Placebo & 3 different doses of 3mg/kg, 6mg/kg, 10mg/kg were administered intravenously every month in 165 patients in 33 sites of USA over the course of 1 year. The results came out fairly positive, showing significant reduction in the Aβ plaques. A comparative study of brain scan images of Alzheimer’s patients before and after the treatment is given in Figure-2. Common side effects of the treatment were ARIA (Amyloid related imaging abnormalities), headache, UTI (Urinary tract infection) & upper respiratory tract infection.

 

 

Figure 2.  PET (Position Emission Tomography) images of the Alzheimer’s patients before and after Aducanumab treatment. Red color indicating the plaque.⁴

 

Though many more steps and trials are required to finally approve the drug for its intended use, it’s very encouraging that we may finally have a treatment for Alzheimer’s disease that after decades of efforts. So, it can be hoped now that in a few years, there will be a drug to use against Alzheimer’s disease which will  save many lives & bypass a significant amount of  sufferings. It seems like the prayers of Alzheimer’s patients & their families are finally answered.

 

References:

1. World Health Organization (WHO), web accessed on 9/25/2018
   http://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
    
2. Kristin R Wildsmith, Monica Holley, Julie C Savage, Rebecca Skerrett and Gary E Landreth (2013). “Evidence for impaired amyloid β clearance in Alzheimer’s disease”. Alzheimer’s Research & Therapy. 5:33
    
3. Hooper NM (2005). “Roles of Proteolysis and Lipid Rafts in the Processing of the Amyloid Precursor Protein and Prion Protein”. Biochemical Society Transactions. 33(Pt 2):335–38
    
4. Jeff Sevigny, Ping Chiao, Thierry Bussière, Paul H. Weinreb, Leslie Williams, Marcel Maier, Robert Dunstan, Stephen Salloway, Tianle Chen, Yan Ling, John O’Gorman, Fang Qian, Mahin Arastu, Mingwei Li, Sowmya Chollate, Melanie S. Brennan, Omar Quintero-Monzon, Robert H. Scannevin, H. Moore Arnold, Thomas Engber, Kenneth Rhodes, James Ferrero, Yaming Hang, Alvydas Mikulskis, Jan Grimm, Christoph Hock, Roger M. Nitsch2, Alfred Sandrock (2016). “The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease”. Nature. 53: 50-57
    
    
   By Iris Begum, a PhD student in Chemistry at the University of Kentucky
    

Opioid Dependency: Choice or Disease

One of the most talked about topics when looking at the demographics of rural communities—especially those in the regions of Kentucky, West Virginia, Virginia, and Tennessee—is the growing epidemic of opioid addiction. A very heavily debated topic centered around addiction being a choice or a disease has sparked controversy over how to treat individuals who have opioid dependency. So, what is it that makes opioid addiction so prominent in society? To answer this question, we must first understand how opioids work.

Within the central nervous system, there are three types of opioid receptors—mu, delta, and kappa¹. Of these 7-transmembrane G-protein coupled receptors (GCPRs), the mu opioid receptor is the one that tends to have the higher affinity for opioids such as morphine¹. Once activated, a downstream inhibitory process is activated by way of inactivating adenylate cyclases within the affected cell². Once this happens, the release of neurotransmitters is inhibited which affects the transmission of pain to the thalamus at the junction of the peripheral nerves and the central nerves within the dorsal horn². This decrease of sensation is what gives opioids their analgesic affects which may lead to dependency and addiction.

The question remains of how individuals become addicted to these substances if their sole purpose is to manage pain. Social interactions are thought to be the underlying cause for most addictions³. However, there are many other ways that someone can become addicted to a substance. With opioids being used to treat pain, there is always the chance that someone can become addicted without even realizing it.

Often, dependency can be seen when someone who has been treated with opioids for pain stops receiving treatment. The seemingly immediate adenylate cyclase activity that allows for neurotransmitter release will begin opioid withdrawal symptoms and make the individual feel like they’re in pain¹. With proper medical intervention, the addiction from this point can be avoided. However, the easy access to synthetic opioids such as fentanyl allows for individuals to continue receiving “treatment” without prescriptions⁴.

Figure 1 shows a sharp increase in overdose death rates of opioids between 2000 and 2016. A sharp increase can also be seen for the other synthetic opioids such as fentanyl⁴.

With dependency comes tolerance as well. This happens when an individual loses the desired effect of a drug with administration of the normal dose. Continued use of opioids, whether prescribed or obtained illegally, can lead to the individual developing tolerance for the normal recommended dose for treatment at which point they administer more to get the desired effect¹. The increase in dosage at this point is what eventually leads individuals to overdose, which is why opioid related overdoses have increased in recent years. According to the CDC, the number of deaths related to opioid addiction increased to approximately 15 deaths per 100,000 people between 2000 and 2016⁴. This increase in overdoses as well as constant treatment of opioid withdrawals is what makes people question whether this is a disease or just a choice.

Regardless of one’s point of view, it is certain that the growing epidemic of overdoses by use of opioids is cause for concern. Researchers are finding new substances each day to help combat this crisis, such as AT-121 which was discovered to be a dual action analgesic and opioid antagonist by the Wake Forest Baptist Medical Center thus allowing an individual to receive the desired analgesic effect without concern of addiction³_. However, until these types of drugs are approved for clinical use by the FDA, it is important to recognize the impact that opioids can have on communities. Especially those who may have easier access to them than most.

 

1. Chahl, L. A. “Opioids- mechanism of action.” Australian Prescriber, 30 Jun. 1996, pp.63-65. Accessed 16 Sep. 2018. Web. https://www.nps.org.au/australian-prescriber/articles/opioids-mechanisms-of-action
2. Pathan, H. and Williams, John. “Basic opioid pharmacology: an update.” British Journal of Pain. Feb 2012, 6(1): 11-16 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590096/
3. Mayo Clinic Staff. “Drug addiction (substance use disorder)” Web. Accessed 9/14/18. https://www.mayoclinic.org/diseases-conditions/drug-addiction/symptoms-causes/syc-20365112
4. Center for Disease Control. “Opioid Data Analysis and Resources” Web. Accessed 9/14/2018. https://www.cdc.gov/drugoverdose/data/analysis.html
5. Wake Forest Baptist Medical Center. “Scientists take big step toward finding non-addictive painkiller.” Science Daily, 29 August 2018. www.sciencedaily.com/releases/2018/08/180829143821.htm

By Dalton Hall, Master's of Medical Sciences Student, University of Kentucky