- Renishaw plc’s convection-enhanced delivery
device results in accurate targeting and distribution of MANF to
Parkinson’s disease-associated brain areas -
Amarantus Bioscience Holdings, Inc. (OTCQX:AMBS), a
biotechnology company developing therapeutic and diagnostic product
candidates in orphan indications and neurology, announced the
publication of a study demonstrating the targeted delivery of
mesencephalic-astrocyte-derived neurotrophic factor (MANF) to brain
regions associated with Parkinson’s disease in a porcine model. The
paper entitled, “Convection-enhanced delivery of MANF – volume of
distribution analysis in porcine putamen and substantia nigra1,”
from the collaboration with Renishaw plc's (LON:RSW)
Neurological Applications Department and the Functional
Neurosurgery Research Group at the University of Bristol, was
published in the Journal of the Neurological Sciences.
The publication reports for the first time the
distribution of MANF in putamen and substantia nigra following
convection-enhanced delivery (CED) in a large animal model and
confirms the potential of targeted infusion of MANF as a novel
treatment strategy for PD. The study demonstrates that: (i) MANF
can successfully be delivered to the porcine putamen and substantia
nigra, the brain areas centrally involved in PD, and (ii) that
pharmacologically meaningful volumes of distribution of MANF can be
achieved using Renishaw's convection-enhanced delivery device
currently in human clinical development.
“Our decades-long human experience with
convection-enhanced delivery of protein therapeutics taught us that
the therapeutic potential of neurotrophic factor treatment of PD is
heavily dependent on the ability to accurately and effectively
target the affected brain regions,” said Prof. Steven Gill, MB,
FRCS, MS, honorary professor of neurosurgery at the University of
Bristol. “These published data confirm the translational potential
of CED of MANF as a novel treatment strategy in PD.”
“We now have definitive confirmation that MANF
can be precisely and accurately delivered to specific sites in the
brain that are affected by Parkinson’s disease. Moreover, MANF can
be distributed via CED in a volume thought to elicit a
therapeutic effect,” said Gerald E. Commission, President & CEO
of Amarantus. “The availability of an accurate and effective
targeting method to deliver MANF to the brain is an important step
for the development of MANF in PD. We believe these data provide a
firm basis for studies in non-human primates as well as subsequent
human clinical trials.”
Study SummaryThe porcine model
is increasingly being used in neuroscience research as the large
brain volume and similarity of cortical and subcortical anatomy to
the human brain may offer increased translational relevance over
rat and non-human primate models. The aims of this recently
published study using convection enhanced delivery (CED) in pig
brains were two-fold: (1) To assess the targeting and to determine
distribution volumes of MANF in porcine putamen and substantia
nigra and (2) to correlate the distribution volumes of MANF with
co-infused gadolinium-DTPA.
Using a recessed-step catheter design it was
possible to achieve reflux-free infusions in both putamen and
substantia nigra. The volumes of distribution of gadolinium-DTPA
and MANF were determined by real-time magnetic resonance imaging
(MRI) and immunohistochemical analysis, respectively. The authors
concluded that the distributions of gadolinium-DTPA and MANF
correlated well and that co-infusion of gadolinium as a proxy
measure of MANF distribution in future clinical studies is
supported by these data.
CED of MANF resulted in an effective
distribution within the target regions of the brain as evidenced by
immunohistochemical staining. Comparison of the MANF diffusion (Vd)
and infusion (Vi) volumes indicated an approximate (Vd:Vi) ratio of
3 in the putamen and 2 in the substantia nigra. The volume of the
substantia nigra pars compacta (SNpc) in patients with PD has
recently been reported as less than 120 mm3. An extrapolation of
the results from this present study indicates that with a single
catheter targeted to the human SNpc and assuming a Vd:Vi ratio of
2, it may be possible to distribute MANF throughout this target in
approximately 30 minutes using a maximum infusion flow rate of 5
ml/min. Similar considerations apply to the delivery of MANF to the
human putamen. Infusion times in the range of 30 to 120 minutes are
likely to be acceptable to patients and reports are emerging of
using faster flow rates safely in the human putamen which would
further reduce the infusion time. Moreover, pre-clinical data from
a rat PD disease model suggests that only a fraction of the
striatal volume needs to be targeted to elicit a pharmacological
effect.
The abstract, “Convection-enhanced delivery of
MANF – volume of distribution analysis in porcine putamen and
substantia nigra,” may be accessed online via the Journal of the
Neurological Sciences at
http://www.jns-journal.com/article/S0022-510X(15)00477-3/abstract.
1N.U. Barua, A.S. Bienemann, M. Woolley, M.J.
Wyatt, D. Johnson, O. Lewis, C. Irving, G. Pritchard, S.Gill,
Convection-enhanced delivery of MANF – volume of distribution
analysis in porcine putamen and substantia nigra, Journal of the
Neurological Sciences (2015), doi: 10.1016/j.jns.2015.08.003.
About Parkinson's Disease
Parkinson's disease is a chronic, progressive neurological disorder
that causes motor symptoms such as tremors, rigidity and slowed
movements as well as non-motor symptoms including cognitive
impairment and autonomic dysfunction. The Parkinson's Disease
Foundation estimates that there are approximately one million
people living with PD in the United States and seven to ten million
PD patients worldwide. The most commonly prescribed treatments for
PD are levodopa-based therapies. There is currently no cure
available for Parkinson's disease.
About Mesencephalic-Astrocyte-derived
Neurotrophic Factor (MANF)MANF
(mesencephalic-astrocyte-derived neurotrophic factor) is believed
to have broad potential because it is a naturally-occurring protein
produced by the body for the purpose of reducing and preventing
apoptosis (programmed cell death) in response to injury or disease,
via the unfolded protein response. By manufacturing MANF and
administering it to the body, Amarantus is seeking to use a
regenerative medicine approach to assist the body with higher
quantities of MANF when needed. Amarantus is the front-runner and
primary holder of intellectual property around MANF, and is
initially focusing on the development of MANF-based protein
therapeutics. MANF was discovered utilizing Amarantus' proprietary
PhenoGuard™ Protein Discovery Engine.
MANF's lead indication is retinitis pigmentosa,
and additional indications including Parkinson's disease, diabetes
and Wolfram's syndrome are currently being pursued. Further
applications for MANF may include Alzheimer's disease, traumatic
brain injury, myocardial infarction, antibiotic-induced ototoxicity
and certain other rare orphan diseases currently under
evaluation.
About Amarantus BioScience Holdings,
Inc.Amarantus BioScience Holdings (OTCQX:AMBS) is a
biotechnology company developing treatments and diagnostics for
diseases in the areas of neurology and orphan diseases. The Company
has an exclusive worldwide license to intellectual property rights
associated to Engineered Skin Substitute (ESS), an orphan drug
designated autologous full thickness skin replacement product in
development for the treatment of adult severe burns currently
preparing to enter Phase 2 clinical studies. The Company is
currently evaluating human clinical data from previously conducted
studies in pediatric severe burns and Congenital Giant Hairy Nevus
to support clinical development expansion into those areas.
AMBS also has development rights to eltoprazine, a small molecule
currently in a Phase 2b clinical program for Parkinson's disease
levodopa-induced dyskinesia with the potential to expand into adult
ADHD and Alzheimer's aggression. AMBS owns the intellectual
property rights to a therapeutic protein known as
mesencephalic-astrocyte-derived neurotrophic factor (MANF) and is
developing MANF as a treatment for orphan ophthalmic disorders,
initially in retinitis pigmentosa (RP) and retinal artery occlusion
(RAO). AMBS also owns the discovery of neurotrophic factors
(PhenoGuard™) that led to MANF's discovery.
AMBS' Diagnostics division owns the rights to
MSPrecise®, a proprietary next-generation DNA sequencing (NGS)
assay for the identification of patients with relapsing-remitting
multiple sclerosis (RRMS) at first clinical presentation, has an
exclusive worldwide license to the Lymphocyte Proliferation test
(LymPro Test®) for Alzheimer's disease, which was developed by
Prof. Thomas Arendt, Ph.D., from the University of Leipzig, and
owns intellectual property for the diagnosis of Parkinson's disease
(NuroPro).
For further information please visit
www.Amarantus.com, or connect with the Company on Facebook,
LinkedIn, Twitter and Google+.
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Investor and Media Contact:
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Jenene Thomas Communications, LLC
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