later, it was reported that UniCure has begun manufacturing runs at a new plant in Massachusetts.)
Not sure what this particular optimism is based on,
but in a Bloomberg Business article, Gbola Amusa,
MD, CFA, the head of health care research at Chardan Capital Markets in New York, NY, suggested
that the cost of Glybera “is likely to be far above the
price of future gene therapies.”6
Gene therapy treatments are in development
for a wide array of illnesses, including a dozen or
more products in late-stage clinical development
for the treatment of cancer, ocular, and cardiovascular disorders. One therapy that may soon get
EU approval is from GSK and treats patients with
adenosine deaminase for severe combined immunodeficiency syndrome. A recent market research
report identified a total of 483 gene therapy
molecules in the market or clinical pipeline, most
in early development. There are a handful of gene
therapies approved for use in China, Russia, and the
Philippines.
How Can You Mend a Broken Heart?
Optimal heart function is dependent on, among
other things, healthy cardiomyocytes. Progressive
changes in cardiomyocyte phenotype are a central
feature in chronically stressed and failing hearts, as
is cell death.
Damage to the cardiomyocyte population comes
in several forms. The human left ventricle has 2
to 4 billion cardiomyocytes, 25% of which can be
wiped out with a single myocardial infarction.7 Cardiomyocyte hypertrophy is also seen in physiologic
settings: 20 million are lost yearly due to aging, for
example, and pregnancy and athletic challenges
may result in cell loss, too. But it’s the chronic
stress and overload conditions seen in HF and its
predecessors that really cause problems. Regenerating or repairing damaged myocytes has been an
important theme in cardiovascular research.
Unfortunately, the heart is one of the least
regenerative organs in the body. Traditionally, the
heart has been thought of as a terminally differentiated postmitotic organ in which the number of
cardiomyocytes is established at or near birth. Researchers now know that cardiac stem cells reside
in the heart and have the ability to differentiate into
cardiomyocytes, allowing for some—albeit limited
and slow—regeneration.8
Cell therapy relies on the administration of live
whole cells or maturation of a specific cell population to repopulate areas of damaged myocardium.
Despite extensive efforts, no cell therapy has been
conclusively shown to be effective.9
Gene therapy, on the other hand, focuses not on
replacing lost cardiomyocytes but rather on improving the function of existing myocytes by altering or
influencing the expression of specific genes. Some
approaches try to introduce a new gene into the
body to help fight a disease.
Sometimes a combined approach works best,
making it hard to categorize an approach as clearly
28 CardioSource WorldNews
cell or gene therapy. In
FIGURE 2 CUPID LVEF by Treatment Group9
May, phase II results were
presented at Heart Failure
2015 showing the potential
of a novel non-viral gene
therapy that expresses
stromal cell-derived factor-1
(SDF-1), a naturally occurring signaling protein that
repairs damage by recruiting circulating stem cells to
the site of injury.
The therapy, called
JVS-100 (Juventas Therapeutics, Cleveland, OH),
is a deoxyribonucleic acid
FIGURE 3 CUPID Recurrent Events
plasmid designed to be
delivered directly to the site
of injured tissue. The trial,
called STOP-HF, showed
that a single treatment of
15 mg or 30 mg SDF-1
(delivered to the heart as 15
injections using an endocardial injection catheter) did
not significantly improve
the composite endpoint of
6-minute walk distance and
quality of life compared
to placebo (the primary
endpoint), but at its highest dose and in the sickest
patients (left ventricular
(Barry Greenberg, MD at ESC 2015)
ejection fraction [LVEF]
< 26%), it did significantly
increase LVEF compared
to placebo at 1 year. The
therapy appeared safe and the development of
Celladon
JVS-100 continues.
When biotech companies fall, they fall hard.
Unrealistic valuations help, as do politicians trying
to score points with voters. But the real issue for
Squeeze and Release
these companies is that they often have no sales or
Calcium cycling is central to cardiomyocyte funcrevenue and only one or two drugs in the pipeline.
tion and a popular target for gene therapy. During
If a key compound fails to meet an endpoint in a
each heartbeat, calcium (Ca2+) is taken up and
phase II or III clinical trial, stock prices commonly
then released from the sarcoplasmic reticulum
drop 50% or more.
(SR). Calcium handling in HF-damaged cardiomyoNot long ago San Diego-based Celladon was
cytes is impaired, producing a weak contractile
a biotech darling in the gene therapy space. Its
force. Also, impaired calcium uptake to the SR
targeted therapy, called Mydicar, was designed
results in incomplete myocyte relaxation after conto enhance the contractile potential of remaining
traction. Calcium cycling is a popular gene therapy
cardiomyocytes in individuals with HF.
target for HF and the focus of two of the compaWe noted above that deficient SR calcium uptake
nies profiled below: Celladon and Renova.
has been identified in failing hearts. The sarcoplasThe field is an interesting mix of traditional
mic/endoplasmic reticulum Ca2+ -ATPase (SERacademic research and Silicon Valley-type startCA2a) enzyme causes muscle relaxation by lowerups with bubbly valuations, news-making parting levels of cytosolic calcium and restoring calcium
nerships, and loads of entrepreneurial spirit. But
the level of expertise needed to develop a success- reserves in the SR. A decrease in SERCA2a activity
has been shown to be responsible for abnormal
ful product—expertise not only in gene therapy
calcium homeostasis i n failing hearts. Conversely,
but also in product development and product
registration—makes for a field that demands high overexpression of SERCA2a boosts contractility.
The concept behind Mydicar was that overexperformers, generous funding, and the possibility
pression of the SERCA2a gene in the myocardium
of abject failure.
January 2016