Final Preclinical Asthma Study Confirms Efficacy
12 December 2017 - 11:24AM
Australian stem cell and regenerative medicine company, Cynata
Therapeutics Limited (ASX:CYP), is pleased to announce that it has
received the final report on the effects of Cymerus MSCs in
combination with or in comparison to the corticosteroid
dexamethasone in a further preclinical asthma study.
Corticosteroids are considered to be the most effective
medications for controlling asthma (when taken regularly).
The study was conducted under the supervision of
Associate Professor Chrishan Samuel and Dr Simon Royce of the
Monash Lung Biology Network,2 using a well-established mouse model
of chronic allergic airways disease, which closely resembles asthma
in humans, and includes several key features: airway inflammation;
airway remodelling/fibrosis (structural changes in the airways due
to excess fibrous tissue); and airway hyperresponsiveness.
Daily administration of dexamethasone (a
corticosteroid), demonstrated marked anti-inflammatory effects in
this model. It reduced airway inflammation by approximately 55% and
airway inflammation-induced goblet cell metaplasia (abnormal
changes in the cells responsible for producing mucus) by
approximately 80% (both p<0.001 vs untreated mice). However,
dexamethasone displayed weak anti-remodelling and anti-fibrotic
effects, and only reduced airway hyperresponsiveness by
approximately 30% over the 2 week-treatment period.
In comparison, once-weekly administration of one
million Cymerus MSCs resulted in striking reductions of airway
remodelling, fibrosis and airway hyperresponsiveness. Most notably,
subepithelial collagen deposition (a measure of fibrosis) and
airway TGF-β1 expression levels (a measure of airway remodelling)
were normalised to levels equivalent to mice in which asthma had
not been induced, while airway hyperresponsiveness was reduced by
70-75% (all p<0.001 vs untreated mice).
When the two treatments were combined, a
pronounced synergistic effect was achieved, resulting in similar
anti-inflammatory effects to dexamethasone alone and similar
reductions in remodelling, fibrosis and airway hyperresponsiveness
to Cymerus MSCs alone.
Summary of Results
|
Dexamethasone alone |
Cymerus MSCs alone |
Combination |
Airway inflammation |
** |
* |
** |
Goblet cell metaplasia |
** |
- |
** |
Airway remodelling |
* |
*** |
*** |
Fibrosis |
* |
*** |
*** |
Airway hyperresponsiveness |
* |
** |
** |
Key: The * symbol represents a reduction of the
relevant feature, and the number of asterisks represents the
relative extent of reduction. Each feature listed is a
negative manifestation in the asthma model, so in all cases a
decrease is a positive outcome. |
“The combination of Cymerus MSCs and
dexamethasone resulted in maximal improvement for each endpoint
measured. Hence, it can be concluded that such a combination
therapy has the potential to improve treatment outcomes in
asthmatic patients,” said Associate Professor Samuel.
Dr Kilian Kelly, Cynata’s Vice President,
Product Development commented: “These findings further strengthen
the body of evidence supporting the use of Cymerus MSCs as a
potential asthma treatment. In addition to confirming that Cymerus
MSCs had a greater effect than corticosteroid treatment on several
key manifestations of asthma in this model, these results provide
clear evidence that Cymerus MSCs can work in synergy with
corticosteroids. Overall, the results suggest that Cymerus MSCs
could be used as a standalone treatment, for example in patients
who are unable to tolerate corticosteroids, or as an add-on therapy
in patients who are unable to gain control of their condition with
existing medications.”
CONTACTS: Dr Ross
Macdonald, CEO, Cynata Therapeutics: Tel: +61 (0)412 119343; email
ross.macdonald@cynata.comDaniel Paproth, Australia Media Contact,
+61 (0)421 858 982, daniel.paproth@mcpartners.com.auLaura Bagby,
U.S. Media Contact, 312-448-8098, lbagby@6degreespr.com
About Cynata Therapeutics
(ASX:CYP)Cynata Therapeutics Limited (ASX:CYP) is an
Australian clinical stage stem cell and regenerative medicine
company that is developing a therapeutic stem cell platform
technology, Cymerus™, originating from the University of
Wisconsin-Madison, a world leader in stem cell research. The
proprietary Cymerus™ technology addresses a critical shortcoming in
existing methods of production of mesenchymal stem cells (MSCs) for
therapeutic use, which is the ability to achieve economic
manufacture at commercial scale. Cymerus™ utilises induced
pluripotent stem cells (iPSCs) to produce a particular type of MSC
precursor, called a mesenchymoangioblast (MCA). The Cymerus™
platform provides a source of MSCs that is independent of donor
limitations and provides an “off-the-shelf” stem cell platform for
therapeutic product use, with a pharmaceutical product business
model and economies of scale. This has the potential to
create a new standard in the emergent arena of stem cell
therapeutics and provides both a unique differentiator and an
important competitive position.
About the Preclinical Study in the Ovalbumin-Induced
Allergic Airways Disease ModelFemale wild-type BALB/c mice
at 7–8 weeks of age were maintained under specific pathogen-free
conditions, under a fixed lighting schedule with access to food and
water ad libitum. A well-established ovalbumin-induced chronic
allergic airways disease model was used as previously described.3
Briefly, mice were sensitised with intraperitoneal injections of
ovalbumin and alum on days 1 and 14, and then challenged with a
nebulised aerosol solution of ovalbumin for 30 minutes, three
times a week for 8 weeks (from days 21 to 77). The study involved a
total of 40 mice, which were randomly assigned to one of the
following five groups (eight animals per group):
- Untreated controls (no asthma)
- Untreated sensitised animals (asthma)
- Sensitised animals (asthma), treated with IN infusion of
MSCs
- Sensitised animals (asthma), treated with IN infusion of
DEX
- Sensitised animals (asthma), treated with IN infusion of MSCs +
DEX
All MSC-treated animals received a dose of 1 million cells by
the specified route of administration on two occasions (once weekly
from weeks 9-11). DEX (0.5mg/ml) was administered once daily from
weeks 9-11.The following endpoints were then measured at week 11
(after 2-weeks of MSC ± DEX treatment):
- Inflammation score – as a measure of airway inflammation
(AI)
- Goblet cell metaplasia – as a measure of AI-induced airway
remodelling (AWR)
- Epithelial thickness – as a measure of AWR
- Sub-epithelial collagen thickness – as a measure of
AWR/fibrosis
- Total lung collagen concentration – as a measure of
AWR/fibrosis
- Epithelial TGF-β1 staining – as a measure of AWR
- Subepithelial myofibroblast density – as a measure of AWR
- Gelatinase (MMP-2 and MMP-9) expression/activity – as a measure
of AWR
- AHR/reactivity in response to the bronchoconstrictor
methacholine, measured by invasive plethysmography (a measure of
lung function).
1 The Global Asthma Report - 2014
2 The Monash Lung Biology Network is a consortium, which
includes researchers from the Biomedicine Discovery Institute and
Department of Pharmacology at Monash University, Melbourne.
3 Temelkovski J et al. An improved murine model of asthma:
selective airway inflammation, epithelial lesions and increased
methacholine responsiveness following chronic exposure to
aerosolised allergen. Thorax. 1998;53(10):849‑56.