Uniqure and the Celladon Legacy

Virus-based gene therapies are demonstrating strong proof-of-concept primarily for hematological diseases. To date, however, the data targeting solid organs has been weak. This was best exemplified by the recent results for Celladon’s Mydicar therapy providing AAV-mediated SERCA protein expression for heart failure (HF) patients. As readers might recall, prior posts outlined that Celladon’s preclinical data were exceptionally weak and failed to show increased target protein expression. Without this, there was little reason to expect success in their randomized CUPID-2 trial regardless of the results in the dose-finding CUPID-1 trial. CUPID-2 ended with a hazard ratio of 0.93 in a modified intent-to-treat population, confirming that the “therapy” was effectively a placebo. This outcome strongly encourages future investors in HF-targeted gene therapies to ensure that the preclinical data achieves one fundamental observation: verifiable change in expression of the targeted protein.

In addition to their hematological programs, European outfit Uniqure is also directing their AAV efforts to address heart failure. Based on their preclinical publications, Uniqure have seemingly come out ahead where Celladon clearly failed. Uniqure’s proof-of-concept studies in pigs receiving their AAV9-based construct to increase S100A1 protein expression seems both reliable and conclusive. At multiple points throughout this publication, the authors are able to show convincing evidence of S100A1 protein at levels above and beyond baseline. Why have Uniqure succeeded in providing convincing proof-of-concept where Celladon have failed? Although Uniqure is using an AAV2/9 construct whereas Celladon opted for AAV2/1, I do not think this makes a material impact. Preclinical data testing the tropism of these vectors have shown that both can target the heart efficiently in rodents, suggesting that the choice of capsid type is not the discriminator. Rather, Uniqure’s retroinfusion with accompanying left anterior descending (LAD) coronary occlusion is likely the key factor. Celladon’s preclinical and clinical data have conclusively shown that intracoronary infusion of AAV is not sufficient to transduce the myocardium, and Uniqure’s modification of working in a retrograde fashion is a novel and effective means of addressing delivery. Although not as simple and convenient as a daily pill, the infusion / temporary LAD occlusion method used by Uniqure is achievable and, given the state of the technology, necessary to achieve transduction of the myocardium and target protein expression.


Although Uniqure and their team are to be commended for their technical achievement and thorough preclinical work, I remain skeptical of the S100A1 program and, by extension, their collaboration with Bristol-Myers Squibb. Although this blog attempts to be as quantitative and data-driven as possible, the reservations surrounding these programs are, admittedly, qualitative and a “gut” feeling.

To add context to the gut feeling, we can set the stage for what these programs are attempting to achieve. Simply put, both programs from Uniqure and Celladon were attempting to restore what was once abundant. In the case of Celladon, they were attempting to capitalize on literature observations that the expression of SERCA2a declines in the context of the failing heart. Similarly, Uniqure is pointing to a decrease in S100A1 in the failing heart as a point of intervention. Simply put, this approach relies on an underlying belief that restoring something to the levels found in the “normal” heart will allow the failing heart to recover some or all of its lost function. In effect, the strategy treats heart failure as if it was analogous to the pathophysiological settings wherein enzyme replacement therapies succeed. Missing glucocerebrosidase because you have Gaucher’s disease? We can provide the enzyme to attempt to restore it to physiological levels. Is your failing heart low on S100A1? We have an AAV for you. Unfortunately, I think this strategy is very flawed when applied to heart failure.


It is very well established that heart failure impacts the heart in a myriad of ways. At the molecular level, we can observe changes in protein signaling and protein abundance. But at a more macro level, there are clear structural changes that occur. The figure from Wikipedia does a good job of showing representative structural changes and remodeling that are evident in various pathophysiological states. 

Simply put, this figure is the backbone for my skepticism. If we take the example of S100A1, the preclinical data suggest that ischemia-induced HF (which often takes a first step through hypertrophy) induces a state of the heart wherein S100A1 expression level is less than it was under normal conditions. Therefore, the presumption is that increasing S100A1 in the hypertrophic or failing / remodeled heart will allow the heart to return to normal. This, in my view, is a logical flaw. In effect, I believe this reflects a cognitive dissonance that treats the remodeled heart as simply a normal heart with reduced S100A1 (or reduced SERCA2a, or reduced protein X) expression. However, this simply isn’t true. The remodeled heart has altered structure including myocyte disarray, aberrant signaling, and changes in the expression level of a myriad number of proteins. In effect, the context has changed. As a simple analogy, consider the case of the smoker who develops emphysema. At the point of emphysema diagnosis, quitting smoking will not simply reverse the course of disease. The damage is done, alveoli and capillary beds have expired. In effect, cessation of smoking by an emphysematic patient does not have the same effect as cessation of smoking for someone who has not yet developed emphysema. The contexts have changed, and therefore the treatment and care strategies are not simply interchangeable. Similarly, my contention is attempting to “restore” a singular protein level to that found in the normal heart provides no guarantee of recovery for a remodeled heart. In support of this argument for S100A1 specifically, human heart tissue from nonfailing, failing and left ventricular assist device (LVAD) supported hearts show that although there is a decrease in inotropic response and S100A1 protein in failing hearts, LVAD supported hearts demonstrated restored inotropic response yet no restoration of S100A1. In that respect, these human tissue data suggest a peripheral rather than pivotal role for S100A1.


The counterpoint to this is, obviously, the hundreds of mouse and porcine studies showing that restoration of intracellular protein X to the failing heart restores function and rescues the model. But the level of success of each and every one of these studies is reason to be highly skeptical and, to a certain extent, dismissive of the “restoration of protein X rescues the heart” narrative. Additionally, consider the drugs used in the clinic for patients with / developing heart failure. By and large, they impact whole intracellular signaling cascades through modulation of surface receptors rather than focus on restoration of a single intracellular protein. Even in that context, the HR benefit is around 20%. Therefore, if manipulation of a whole signaling pathway in the heart yields a 20% benefit, what can reasonably be expected from focusing on an individual intracellular protein?