SERCA targets in HF

Question 1

Delmonte et al 2004

Answer 1

Hypothesised that overexpression of the sarcoplasmic reticulum Ca(2+) ATPase pump (SERCA2a) may improve both contractile dysfunction and ventricular arrhythmias. Continuous ECG recordings were obtained in 46 conscious rats after adenoviral gene transfer of either SERCA2a 48 h before and 48 h after ligation of the left anterior descending artery. Sham-operated animals were used for comparison for hemodynamic measurements. On ECG, the SERCA reduced the amount of arrhythmia after the MI, and reduced the MI size compared to SHAM

Question 2

Chen et al 2004

Answer 2

Overexpression of SERCA in transgenic rats. Constitutive cardiac SERCA2a overexpression has a transient beneficial effect on remote myocardium function in rat MI, with no improvement in LV global function or prevention of LV remodelling and failure. This benefit is associated with a higher risk of acute mortality, which is prevented by lidocaine treatment. This could be due to reduced NCX activity, leading to adverse electrical remodelling, QT prolongation and torsade de points

Question 3

Kawase et al 2008

Answer 3

Prior studies have reported the beneficial effects of short-term SERCA2a overexpression in rodent models. However, the effects of long-term expression of SERCA2a in pre-clinical large animal models are not known. Using a large-animal, volume-overload model of HF, they report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function potentially prevented diastolic dysfunction, and improved ventricular remodeling. There was no histopathological evidence of acute myocardial inflammation or necrosis.

At 2 months there was an improvement in contractile function and restoration of ventricular function at 4 months

Question 4

Jaski et al 2009

Answer 4

CUPID 1

Delivered AAV via intracoronary perfusion to 9 humans with NYHF 3 and above. It was successful and there were no safety issues. This phase also investigated the side effects that occur as dosage levels are increased

Phase 2

Done on a larger cohort of 39 patients, divided into SERCA2a and placebo. There was increase in systolic function in these patients

CUPID 2B

In

Question 5

CUPID 2B- Greenberg et al

Answer 5

In a cohort of over 200 patients, recruited from various clinics in Europe, USA and Israel, a large randomised and blind testing was done. The drug was referred to as MYDICAR However, the findings were disappointing, as although the drug was safe and well tolerated, it failed to reach the primary and the secondary outcomes. Treatment with MYDICAR did not result in an improvement in the primary endpoint of recurrent HF events compared to placebo. MYDICAR to placebo comparison of the secondary endpoint of all-cause death, need for a mechanical circulatory support device, or heart transplant, likewise failed to show a significant treatment effect.

Question 6

AGENT-HF

Answer 6

This was also done at the same time as CUPID 2B, with similar methodology on patients, the only difference was that it was done in France. Unfortunately, the drug provided no benefits either, so the study was stopped early (early termination).

Question 7

Reasons for failure

Answer 7

1. Dosing issues. Maybe the right dose was not identified in the phase 1 trial
2. Post-transcriptional modification of the virus or immunogenicity against
3. Ineffective gene transfer via the intracoronary perfusion
4. Early termination, the study followed for 12 months but this could be longer

A limited amount of DNA that AAVs can carry

A high inflammatory response of the ADs, which limits the time of expression of the transgene.