A Plain English introduction to repurposing drugs and gene therapy

Repurposing of drugs is possibly the best way to develop fresh treatments that do not take many years to come to the market place. Consider this: A repurposed drug already has a history of testing and use by patients so the major costs incurred in bringing these drugs to the commercial market have been paid out and the safety of the drugs proven. This takes care of a large percentage of the mandatory testing and expense legally required before a drug can be licensed for use by the public. The following examples of studies that have been published on the World Wide Web are just the tip of the iceberg as universities and hospitals gear up to study many existing drugs. The information from these studies helped to clarify the role of the protein structure (genes in your DNA) LRRK2.
This gene has been identified in a range of diseases, including Crohn’s, ulcerative colitis and leprosy. Perhaps you may be surprised to see leprosy mentioned- Leprosy has not disappeared from the world but is now known as Hansen’s disease. Tuberculosis and Parkinson’s are also noted for this gene and while LRRK2 mutation is quite common in Parkinson’s patients and gene blocking drugs are showing some promise against it, just how the mutation causes disease is very unclear at the moment.
Researchers at the Francis Crick Institute, GlaxoSmithKline and Newcastle University have been studying LRRK2 in human and mouse macrophages (Macrophages are immune-system cells that seek out and destroy bacteria). The Macrophages were infected with Mycobacterium Tuberculosis (Mtb). They found that LRRK2 acts to prevent crucial steps in eliminating harmful bacteria. Blocking or deleting LRRK2 in these immune cells reduce levels of Mtb. Taking out the LRRK2 gene in mice worked in a similar way that the mice mounted a better immune response to TB and less Mtb in their lungs, up to two weeks after infections compared to control mice.
These findings may explain how LRRK2 inhibitors could treat Parkinson’s. This new insight could shift the focus in Parkinson’s research for the better: The dogma in the Parkinson’s field has been to focus almost exclusively on the neurons in the brain and what causes them to degenerate. This study shows us that thinking more broadly about the events that cause neurodegeneration may reveal answers to Parkinson’s disease which come from immunology.
This could work both ways as LRRK2 drugs developed to treat Parkinson’s could be repurposed to treat TB. With drug resistant TB on the rise there is always room for new treatments and it would be relatively straight forward to get the drug into the TB patient’s system because it would not need to cross the blood-brain barrier like it does in Parkinson’s disease.

Repurposing a Diabetes drug.

A Plain English introduction to repurposing drugs
GLP-1 (glucagon-like peptide-1) receptor agonists are a well-established type of treatment for Type 2 diabetes. Because of their possible actions scientists are now studying the potential of GLP-1 Receptor Agonists for treating neurodegenerative diseases (peptides are strings of amino acids that form the protein structures in our bodies, in this case a protein that improves insulin secretion from the pancreas and Glucagon relates to blood sugar (glucose) control).
The South Korean Biotech company, Peptron, are among the groups achieving positive early results. The original intention was to make an improved generic (cheaper)version of exenatide for treating Diabetes. But along the way, they also discovered neuro-protective benefits. We all know Parkinson’s is caused by the loss of Dopamine producing neurons in our brains. Research has shown that impairment in the insulin pathway might play a role in Parkinson’s and other analyses suggest a link between diabetes and neurodegenerative disorders. GLP-1 receptors are prevalent in the central nervous system and when stimulated they affect several pathways that can improve cell survival rates and promote neuroprotection. Therefore, scientists believe that targeting GLP-1 while serving its original purpose of improving glucose metabolism (in diabetes) can also halt Parkinson’s.
Earlier research had found that pre-treatment with exendin-4 (the natural hormone that exenatide is based on) helps reduce dopaminergic neurodegeneration. Unfortunately, its use in Parkinson’s is negatively affected by its short half-life and the filtering mechanism known as the blood-brain barrier. The barrier blocks molecules from entering the brain and can make it very difficult to deliver therapeutic agents to the central nervous system. Attempting to solve this problem Peptron has developed an extended release formulation of exenatide called PT302.
In a recent study in a rat model of Parkinson’s, researchers noted that a single dose of PT302 maintained high levels of exendin-4 in the rats’ blood plasma for more than twenty days. Even better, following treatment with PT302, rats with a brain lesion experienced a significant increase in brain tyrosine hydroxylase immunoreactivity which is a measure of dopaminergic neurons in the lesion side of the brain (Tyrosine is an amino acid and one of the building blocks of Dopamine).Current treatments for Parkinson’s improve motor and cognitive functions but don’t help with neurodegenerative processes. So, PT302 is confirmed as being able to cross the blood-brain barrier. In 2014, Peptron licensed NIH patents covering exenatide’s use for neurodegenerative disease treatment and more recently extended the license to encompass the delivery and sustained-release use of exenatide.
A team led by University College London reported findings of a phase two trial of Bydureon in 62 patients with moderate Parkinson’s symptoms (Bydureon is a type two diabetes treatment by AstraZeneca). The outcome of this study saw motor-symptom improvement in those taking the drug for a year, and some benefits persisted twelve weeks after participants had stopped taking it.
FierceBiotechResearch is one of the companies that has been moving PT302 towards clinical trials. Parkinson’s is its first target disease but the company plans to explore further, such as multiple system atrophy, traumatic brain injury and Alzheimers.
Lionel Paulo September 2018