Researchers from Johns Hopkins University in Baltimore have coupled (conjugated) two drugs to more effectively treat brain inflammation. The coupled drug (D-mino) is able to cross the blood-brain barrier to target inflammation mediated by the brain’s resident immune cells, microglia.
Inflammation is a common component of most diseases, and is believed to be critical for disease related cell death. In neurological and neurodegenerative conditions like cerebral palsy or Alzheimer’s disease, inflammation is one of the key steps in the pathway to brain cell death.
To produce their drug, the research group used minocycline, a drug which targets microglia-mediated inflammation, and hydroxyl poly(amidoamine) (PAMAM) generation-6 (G6) dendrimers (hereafter referred to as just dendrimers).
Minocycline had previously shown promise for neurological disease treatment, with the ability to cross the blood-brain barrier, but was not able to be used regularly in the clinic due to the high dosage needed to exert an affect leading to side effects. The common central nervous system side effects related to high-dosage regimes include headaches, dizziness, tinnitus, ataxia (lack of muscle coordination – gait abnormality) and vertigo; all of which are reversed soon after ceasing minocycline treatment.
On the other hand, the dendrimers have been shown to have a longer blood-circulation time that minocycline and can also cross the blood brain barrier. This led the researchers to the hypothesis that combination of both drugs through a conjugation reaction may allow the minocycline to be administered at lower doses than previously, thereby avoiding side-effects.
After coupling the two drugs to form the conjugate D-mino, the researchers performed a series of experiments both in vitro and in vivo to establish the drug’s effects. These experiments established that D-mino still has anti-inflammatory effects on microglial cells in a plate, but is also able to reduce inflammation in a cerebral palsy animal model.
The enhanced efficiency when in circulation, plus the ability to cross the blood-brain barrier, along with the beneficial anti-inflammatory effects indicate that D-mino could be used to treat multiple neurological and neurodegenerative conditions.
Route Of Administration
One issue with a lot of new cutting edge therapies is the route of administration. Cell and gene therapies have the potential to revolutionize how we aim to treat neurological conditions, but the invasive procedure of injecting a therapeutic directly into the brain can cause brain damage or fatal injuries by itself.
An overwhelming advantage of therapeutics like D-mino is that they can be administered into the systemic blood flow (through intravenous injection in this case), where they will migrate across the blood-brain barrier.
The conjugated drugs to create D-mino are both repurposed; which means they have already been tested rigorously for toxicities and the dosages at which these are caused has been investigated also.
Therefore, the cost of performing all of these tests has already been covered leaving only potential future pre-clinical research and clinical trials to be funded for any group who wishes to translate this drug into the clinic.
The ‘inflammasome’ (the processes and pathways which regulate inflammation) has been extensively studied in recent years for both diseases of the brain and the rest of the body. Studies have shown that drugs which reduce inflammation in the brain improve cognitive function in animal models of neurodegenerative disease.
At present our ability to treat neurological conditions is limited by multiple factors, including the difficulty in administering a therapy to the brain safely.
The advancements of our knowledge of the inflammasome along with the repurposing and chemical conjugation of drugs shown in this research could result in more effective treatments for these devastating neurological conditions.
Rishi Sharma, Soo-Young Kim, Anjali Sharma, Zhi Zhang, Siva Pramodh Kambhampati, Sujatha Kannan, Rangaramanujam M Kannan
Activated Microglia Targeting Dendrimer-minocycline Conjugate as Therapeutics for Neuroinflammation
Bioconjugate Chemistry: 13 October 2017. DOI: 10.1021/acs.bioconjchem.7b00569
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: Holly Fischer CC BY 3.0