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Heart Failure
SERCA2a Gene Transfer Therapy for Heart Failure
Krisztina M Zsebo, PhD
1
and Brian E Jaski, MD
2
1. CEO and President, Celladon Corporation, La Jolla; 2. Associate Director, San Diego Cardiac Center, San Diego, California
Abstract
Heart failure treatments are limited and the prognosis of patients with advanced heart failure is poor. Interventions that reverse contractile
deficiency are needed. Heart failure has been elucidated at the level of gene expression in cardiac myocytes, with alterations in expression of
calcium-cycling genes one of the best characterized. The sarcoplasmic reticulum (SR) Ca
2+
ATPase pump (SERCA2a) is critical in controlling the
movement of Ca
2+
between the SR and cytoplasm. SERCA2a deficiency is commonly seen in advanced heart failure, driving the systolic and
diastolic dysfunction in failing hearts. Replacement of this single enzyme via gene transfer can correct this dysfunction, restore Ca
2+
homeostasis, and result in significant improvement in cardiac function. Unlike approved inotropic agents, correcting SERCA2a deficiency via
gene transfer improves cardiac contractility, reduces myocardial oxygen consumption, decreases ventricular arrhythmias, and improves
survival. A clinical trial has been initiated in heart failure patients targeting replacement of SERCA2a by gene transfer using the recombinant
adeno-associated virus rAAV1/SERCA2a.
Keywords
Gene therapy, heart failure, SERCA2a, Ca
2+
handling, cardiovascular disease, recombinant adeno-associated virus, clinical trials
Disclosure: Krisztina M Zsebo, PhD, is an employee of Celladon Corporation. Brian E Jaski, MD, has no conflicts of interest to declare.
Received: January 17, 2009 Accepted: February 25, 2009
Correspondence: Brian E Jaski, MD, San Diego Cardiac Center, 3131 Berger Avenue, STE 200, San Diego, CA 92123. E:
bjaski@sdcardiac.com
Despite important therapeutic improvements in pharmacological and In the US, oversight of the clinical development and ultimate approval
device therapies, the prognosis for patients with advanced of new drugs and biological agents comes under the auspices of the
cardiovascular disease is poor, even with optimal pharmacological US Food and Drug Administration (FDA). The FDA is familiar with viral-
and device management. Heart failure continues to be a major cause based therapies from the review of vaccine products and has
of morbidity and mortality in the US. It is the leading medical cause of approved a number of agents based on naturally occurring viruses
hospitalization and is expected to result in an estimated direct and also composed of defined proteins and nucleic acids, as shown in
indirect cost to the healthcare system in 2009 of $37.2 billion.
1
Table 1.
Non-pharmacological therapies (such as heart transplantation and Currently, the most promising of the gene transfer agents is
the use of implantable left ventricular assist devices) are considered recombinant adeno-associated virus (rAAV). Unlike adenoviral vectors,
only in the later stages of the disease, and access to such therapies which were the predominant vectors used in the early days of gene
is restricted to a fraction of patients who could potentially benefit therapy, rAAV vectors are derived from parvoviruses, which have a
from them. Specifically lacking are interventions that reverse the number of clinically favorable attributes. Foremost, they lack
myocardial contractile deficiency that initially created the heart pathogenicity even in their wild-type state, unlike adenovirus vectors or
failure state.
2,3
the approved vaccines listed in Table 1. In addition, rAAV vectors have
minimal immunogenicity, establish stable long-term transgene
In this context, alternative approaches such as cell and gene therapy expression,
4,5
and are non-replicating and non-integrating into the host
have attracted increased attention. Gene therapies have historically genome, thereby obviating the issue of insertional mutagenesis that has
been challenged by ethical concerns over potential manipulation of plagued retroviral-based gene therapies.
6
the human genome. However, in the last decade gene transfer agents
composed of defined sets of proteins and nucleic acids have become Many factors contribute to the success or failure of gene therapies,
available that are much more amenable to rigorous quality control such as the complexity of the biological system being modified (e.g.
and potency assessments than their cell therapy counterparts, which inducing new blood vessel growth for coronary artery disease), the
presents challenges for consistent manufacturability. immunogenicity of the vector system used, the efficiency and safety
46 © TOUCH BRIEFINGS 2009
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