One of the strongest and most persistent trends in medical care is the transition from invasive medical procedures, such as open surgery, to minimally-invasive interventions that typically result in faster procedures with less patient trauma and better outcomes. New minimally-invasive interventions may also enable the treatment of conditions for which no adequate therapy is currently available. Imaging and related technologies are key to guiding minimally-invasive procedures, providing visualization of the target area for treatment, assisting in the proper placement and operation of instruments, and monitoring the progress of the intervention.
In order to optimally perform such interventions,
image guidance, novel interventional instruments and
advanced therapy solutions are required. Philips
Research and GlyGenix Therapeutics will research the
feasibility of using ultrasound technologies to
guide, monitor and control the delivery of
therapeutic DNA to the liver in preclinical studies
for the treatment of Glycogen Storage Disease Type
1a (GSD-1a).
For Philips, involvement in this joint research work
is one of a number of partnerships that will exploit
its advanced focused-ultrasound technology. In
addition to using co-injected microbubbles to induce
sonoporation, it is also exploring the possibility
of using focused ultrasound to release drugs from
drug-loaded microbubbles and nanoparticles to
achieve targeted drug delivery, and the possibility
of using it for thermal ablation therapy. These
initiatives include Philips’ leadership of the
European Union (EU) SonoDrugs project.
Glycogen Storage Disease Type 1a
Glycogen Storage Disease Type 1a (GSD-1a) is caused
by a defective G6Pase gene that prevents the body
from producing an enzyme called
glucose-6-phosphatase. This enzyme plays a critical
role in the conversion of glycogen to glucose in the
liver as the body attempts to maintain an adequate
blood sugar level between meals. Absence of the
enzyme can therefore lead to potentially
life-threatening periods of acute hypoglycemia
(severely reduced blood sugar). Because the
defective gene only impairs the body’s ability to
convert glycogen into glucose and not its ability to
convert excess glucose into glycogen, the disease
also results in excessive glycogen storage – hence
the name Glycogen Storage Disease. This typically
results in enlargement of the liver, kidneys and
small intestine, often with a range of other
debilitating comorbidities.
At present, GSD-1a is only managed, not cured.
Disease management normally involves stringent
dietary regimes to ensure that the body has a
continuous but not excessive supply of glucose from
dietary sugar and starch. This therapy often
involves continuous feeding via nasogastric or
gastrostomy tubes, or regular feeding every few
hours throughout the day and night. Because
treatment must be carried out from a very early age,
the disease is particularly distressing in infants
and children.
GSD-1a is an inherited disease, with children born
to parents who are both carriers of the defective
G6Pase gene having a one-in-four chance of suffering
from it. Although GSD-1a is a rare disease,
currently affecting around 1 in every 100,000 to
200,000 births in the USA, its debilitating nature
and impact on quality of life make it a disease that
demands worthwhile specialist effort to find better
treatments.
Curative gene therapy
One potential cure for GSD-1a is gene therapy, in
which non-defective G6Pase gene is introduced into
liver cells in the form of a plasmid (a typically
circular DNA molecule that is capable of independent
replication). By restoring production of the
glucose-6-phosphatase enzyme in GSD1a patients, the
rigid dietary regimen and associated complications
are eliminated, leading to a cure for the disease.
The challenge is to find a way of delivering the
G6Pase gene to liver cells. One method that has been
explored is to use viral vectors to transport the
gene into the cells. Candidate viruses do exist,
such as the adeno-associated virus (AAV). However,
current gene therapies that use viral vectors to
infect cells may carry the risk of an antiviral
immune or inflammatory response.
Ultrasound-mediated gene delivery
Ultrasound-mediated delivery of genes offers an
attractive alternative that overcomes the concerns
associated with viral vectors and also provides
opportunities to non-invasively target therapy at
specific internal organs. The ultrasound technique
that will be investigated by Philips and GlyGenix
Therapeutics, Inc. relies on a process called
sonoporation.
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Schematic representation of the ultrasound technique called
sonoporation that will be researched by Philips and GlyGenix
Therapeutics for the targeted delivery of genes*.
Sonoporation
involves the use of microbubbles that are co-injected into the
bloodstream along with the therapeutic genes. When they arrive
at the target organ, the microbubbles are subjected to
high-intensity focused ultrasound causing them to rupture. This
increases the permeability of the blood vessel wall and cell
walls in the underlying tissue and facilitates the local uptake
of the therapeutic genes.
*Please note that the various components have not been drawn to
scale. |
Sonoporation involves the use of microbubbles
(microscopic gas-filled spheres made of a
biocompatible material such as phospholipid) that
will be co-injected into the bloodstream along with
the G6Pase gene. Because these microbubbles act as
an ultrasound contrast agent, their arrival in the
liver (and by inference, the arrival of G6Pase at
the liver) can be tracked with an ultrasound
scanner.
When they arrive at the liver, the microbubbles will
then be subjected to high-energy focused ultrasound
pulses at their resonant frequency, causing them to
rapidly expand and contract. If the microbubbles are
close to a cell wall, their physical deformation or
fragmentation increases the porosity of the cell
wall to the G6Pase gene. The exact mechanisms
involved are not yet fully understood, but it may be
that the oscillating microbubbles induce cavitation
or microscopic water jets in the surrounding fluid,
while fragmentation of the microbubbles may create
ballistic fragments that pierce the cell walls. In
this application, the microbubbles therefore act as
both an imaging agent for guided intervention and as
a delivery mechanism for non-invasive therapy. The
same ultrasound scanner will also be used to image
the liver during the procedure.
Partnering for success
As with most rare diseases, clinical expertise on
GSD-1a is concentrated in only a few medical centers
around the world. Philips and GlyGenix Therapeutics
are therefore fortunate in being able to conduct
pre-clinical studies in collaboration with the
Division of Medical Genetics at Duke University
(Durham, North Carolina, USA), which currently
manages the treatment of many GSD-1a patients. This
should make it significantly easier to move from
pre-clinical to clinical trials if the results of
the joint research look promising.
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