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SERCA - LVAD: Lessons learned for gene therapy in heart failure

Heart Failure

Alexander Lyon.jpgProf. Alexander Lyon 

The prematurely terminated SERCA-LVAD trial gives valuable insights into gene therapy for heart failure, says Dr Alexander Lyon (Royal Brompton Hospital and Imperial College London, London, UK) in relation to his late-breaking abstract presentation yesterday (LBT28).

“Down-regulation of the SERCA2a protein affects cardiomyocyte calcium cycling and is a common feature of heart failure,” says Dr. Lyon. “Restoring SERCA2a levels, in this case by cardiac delivery of an adeno-associated virus 1 vector containing the human SERCA2a gene (AAV1/SERCA2a), could improve cardiac muscle strength and stabilise rhythm based on the results from many preclinical studies.” One of three trials investigating this approach, SERCA-LVAD—supported by the British Heart Foundation—was the first trial to evaluate gene therapy for patients with heart failure and a left ventricular assist device. “It was also the first trial prospectively designed to assess gene delivery post-treatment infusion, via either endomyocardial biopsy material or in explanted hearts, in all trial individuals,” comments Dr. Lyon. “Safety was key in our study, because of the unique needs of patients with LVADs, including complex anticoagulation requirements. We also wanted to address the issue of AAV-targeting neutralising antibodies, which, if found to reduce delivery of AAV1 to the heart, will automatically exclude the estimated 50–70% of patients harbouring them from this type of gene therapy.”

Unfortunately, when the CUPID-2 trial failed to show a benefit of AAV1/SERCA2a, it was considered unethical to continue with SERCA-LVAD and recruitment was halted after only five patients had been randomised and treated. “But,” says Dr. Lyon, “we learned some very useful information from these patients. There were no major adverse events or signs of virus-related cardiac inflammation. And in the one patient with neutralising antibodies, there was no evidence of an adverse reaction to gene therapy, suggesting that these antibodies may not be a contraindication to treatment from a safety perspective.” Possibly the most important lesson, however, concerns dose.

“The biggest barrier to effective gene therapy appears to be the delivery of a sufficient dose.”

As Dr. Lyon explains, “Viral DNA was detected in cardiac tissue from two patients but it was at very low levels—with DNA copy number detected being 25–250-times lower than in animal models—confirming findings from the CUPID studies. This strongly suggests that the doses delivered in CUPID-2 and SERCA-LVAD were too low to impact on the underlying pathophysiology and it indicates that we need to find new ways to achieve delivery of clinically effective doses.”