Repurposing drugs to treat neurological diseases
Journal of Neurology
https://doi.org/10.1007/s00415
Repurposing drugs to treat neurological diseases
T. H. Massey 0
N. P. Robertson 0
0 Division of Psychological Medicine and Clinical Neuroscience, Department of Neurology, Cardiff University, University Hospital of Wales , Heath Park, Cardiff CF14 4XN , UK
1 N. P. Robertson
Vol.:(011233456789)
Introduction
The development of new drugs can be expensive: on average,
it costs over $2 billion to take a medication from inception to
clinical practice. Drug discovery is particularly difficult in
neuropsychiatric diseases as targets are often poorly defined,
inaccessible, and not easily assayed. Furthermore, many
neurological diseases progress slowly over many years, often
requiring clinical trials examining efficacy to be large and
have complex end points. However, one way of expediting
drug development is to repurpose drugs from their original
use to a new indication. Multiple examples exist in clinical
medicine: sildenafil was an ineffective angina drug
repurposed for erectile dysfunction; minoxidil was a hypertension
drug repurposed for hair loss. These unexpected therapeutic
discoveries were made serendipitously, and often as
sideeffects in clinical trials. Unbiased, high-throughput screens
are now being used systematically to test libraries of
clinically approved drugs in areas of medicine away from their
usual indications. These screens can generate novel
therapeutic avenues, shed light on molecular pathology, and lead
directly to clinical trials.
This month’s journal club explores three papers
relating to drug repurposing in Neurology. The first two papers
use unbiased cell-based screens of drug/compound
libraries to search for potential therapeutic activities relating to
either Parkinson’s disease or Zika virus infection of neurons,
respectively. The third paper reports a clinical trial of
clemastine, commonly used as an antihistamine, in the
remyelination of optic nerves in multiple sclerosis.
β2A‑drenoreceptor is a regulator
of the α‑synuclein gene driving risk
of Parkinson’s disease
Intraneuronal aggregates of phosphorylated α-synuclein
(Lewy bodies) are found in the brains of patients with
Parkinson’s disease (PD). Disease severity correlates with Lewy
body formation, although there is debate about whether
these aggregates are directly toxic to neurons.
Overexpression of wild-type α-synuclein, either as a result of SNCA
gene duplication/triplication in familial PD or from gene
regulatory variants in sporadic disease, can drive PD.
Furthermore, decreased α-synuclein production correlates with
clinical improvement.
This paper reported a high-throughput screening assay
for compounds that could reduce SNCA gene expression in
human neuroblastoma cell lines. Cells were grown in
multiwell plates, treated with one of 1126 drugs previously tested
for safety in humans, and then harvested for gene
expression analysis. Optimisation and replication of the screen
ultimately identified four drugs that significantly reduced
SNCA mRNA and protein levels in a dose-dependent
manner: three β2-adrenoceptor (β2AR) agonists, including the
common asthma medication salbutamol, and riluzole, a drug
licensed in amyotrophic lateral sclerosis. Conversely, β2AR
inhibition by propranolol, a non-specific β-blocker, led to
increased SNCA mRNA and protein levels. Extending the
observations to animal models, intraperitoneal
administration of β2AR agonist clenbuterol to wild-type mice
significantly reduced SNCA expression in the substantia nigra.
Similar clenbuterol administration to a mouse model of PD
prevented nigral neuronal loss.
Finally, the study took advantage of the Norwegian
Prescription Database (NorPD) which contains all
information about individual prescriptions in Norway since 2004.
Interestingly, if an individual had ever used salbutamol
(n = 619,863), they had a significantly lower incidence of
PD (rate ratio = 0.66, 95% confidence interval 0.58–0.76),
and, conversely, if they had ever used propranolol for at least
1 year (n = 14,794), they had a significantly increased risk of
PD (rate ratio = 2.20, 95% confidence interval 1.62–3.00).
Adjustments were made for age, sex, and level of education,
as well as attempts to control for other potential confounders
such as smoking and essential tremor.
Comment. This study used a well-designed unbiased
screen to discover compounds that can regulate α-synuclein
gene expression. Unexpectedly, these included β2AR
agonists widely used as asthma medications. The correlation of
β2AR agonist use and reduced incidence of PD in the large
Norwegian population fitted in well with the cellular and
animal work presented, although whether SNCA expression
is the critical driver of pathology in sporadic PD is unknown.
Further work is needed to elucidate molecular mechanisms,
but this should not prevent clinical trials of β2AR agonists
in PD being fast-tracked.
Mittal S et al (2017) Science 357: 891–898.
Identification of small‑molecule i (...truncated)