Abstract
Industry Wire
(Sadik H. Kassim)
Science Wire
Giving CUPID a Hand?
Congestive heart failure (HF) is a leading cause of death, affecting more than 20 million people in the Western world. HF commonly occurs after loss of myocardial tissue due to cardiomyopathies or infarctions, and ultimately leads to deterioration of cardiac function and an inability to maintain proper perfusion of organs. Current treatment largely consists of pharmacological management of symptoms, but the prognosis is poor and most patients require frequent, costly hospitalization.
At the molecular level, a key protein intricately associated with HF pathology is the sarcoplasmic reticulum ATPase SERCA2a. This protein sequesters Ca2+ into the sarcoplasmic reticulum; its downregulation in HF results in reduced availability of Ca2+ for cycling back into the cytoplasm for subsequent contraction cycles. Accumulated knowledge of SERCA2a and HF formed the basis of a gene-based therapy to correct direct causes of HF (1).
Recently, a clinical trial termed “Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease” (CUPID; Celladon Corporation) reported data on a phase II assessment of MYDICAR—an adeno-associated virus type 1 (AAV1) vector encoding the SERCA2a gene—in a small cohort of patients with HF (2). The CUPID trial has been a success from a safety standpoint and, importantly, represents the first instance of an AAV vector mediating gene transfer to the human heart. As for treatment effectiveness, there was a lack of vector dose response, and measurements of cardiac blood ejection fraction did not show significant improvement on AAV1.SERCA2a treatment. However, a complex assessment of overall quality of life suggested durable therapeutic benefit was achieved. Unfortunately, due in part to the limited number of trial subjects, any positive effects observed thus far cannot conclusively be ascribed to SERCA2a expression. In addition, it is important to consider that augmenting the levels of one protein alone could limit benefit without corresponding changes in its regulators.
Indeed, several other proteins regulate SERCA2a activity and contribute to the faulty molecular processes observed in failing hearts. In fact, one such SERCA2a regulator—the Ca2+-binding protein S100A1—is another putative therapeutic target currently in the preclinical stage of development (3). Interestingly, the discovery of a novel, direct SERCA2a regulator was reported last month in Nature (4). Kho and colleagues found that the small ubiquitin-related modifier (SUMO1) reversibly interacts with specific lysine residues within the ATPase domain of SERCA2a, and is essential for SERCA2a activity and stability. SUMOylated SERCA2a was detected in normal human cardiac tissue, and levels of both proteins and of SUMOylated SERCA2a were markedly reduced in tissue from human patients with HF and from mouse and pig models of HF. Restoring SUMO1 expression in a mouse model of HF via intravenous injection of an AAV9.SUMO1 vector resulted in notably increased survival and cardiac function by several measures, akin to the impressive results previously obtained on SERCA2a restitution. The vector-induced increase in SUMO1 expression was dose dependent and accompanied by increases in SERCA2a protein levels, suggesting SUMO1 may work to maintain SERCA2a levels in an HF context. One intriguing potential implication of this finding is that perhaps the absence of a proper dose response in the CUPID trial indicates that increasing SERCA2a alone may be inefficient in an HF environment where SUMO1 is also dysregulated.
Taken together, the CUPID trial efficacy results are encouraging, but future confirmatory trials enrolling greater numbers of patients are warranted. Once the extent to which SERCA2a gene replacement improves HF is determined, perhaps combined gene therapeutic approaches will emerge in order to harness maximal restoration of Ca2+ cycling. The SUMO1 results described here, once confirmed in larger animal models that more closely recapitulate human heart physiology and Ca2+ handling, could well end up going the way SERCA2a has paved with the CUPID trial.
The data published in the SUMO1 paper thus define a novel regulatory mechanism of SERCA2a, further expanding the field's understanding of the complex molecular underpinnings that are hallmarks of HF. Gene transfer of SUMO1 may become a future approach for HF treatment, either alone or in combination with SERCA2a modulation. (Rebeca M. Tenney)