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AAV immunity is a significant issue for genetic therapies for all diseases

December 12, 2020
Photo of several children with Sanfilippo Syndrome. AAV immunity is an issue for any patient who receives a gene therapy, including children with Sanfilippo Syndrome.

Glenn and Cara O’Neill, President and Chief Science Officer, respectively, of Cure Sanfilippo Foundation, were honored to be invited by the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) group to speak at their December 2020 “Workshop on Systemic Immunogenicity Considerations for Adeno-Associated Virus (AAV)-Mediated Gene Therapy” regarding systemic AAV gene therapies and the issues around AAV immunity.

A personal story of isolation to save their daughter

During their presentation to NIH/NCATS conference, the O’Neills first shared their isolation story, which happened before quarantine was something globally endured.

In 2014, the ONeills self-isolated to avoid exposing their daughter Eliza to AAV so she could be a candidate in the first-ever gene therapy clinical trial for Sanfilippo Syndrome, Type A. What they expected to be a six-month isolation turned into a staggering 726 days. Four days short of two years. All to give Eliza a chance at life.

An important element of their story: they didn’t know if Eliza had been exposed to AAV and developed antibodies prior to their isolation because patient- or caregiver-initiated testing wasn’t available. And the presence of AAV antibodies makes or breaks a patient’s chance at any AAV gene therapy.

It wasn’t until the O’Neills were months into their isolation, through Eliza’s participation in a natural history study for Sanfilippo Syndrome and the researchers’ willingness to share information, that they found out she did not have AAV antibodies. While that didn’t guarantee that she would be accepted into the Type A clinical trial when it began, it meant she was at least still eligible.

When the time came and the clinical trial was ready, Eliza was still negative for AAV antibodies and passed the trial’s screening. She was treated in the first cohort of children for this first-ever gene therapy for Sanfilippo Syndrome.

“I made it through without breaking down,” shared Glenn O’Neill in a Facebook post after talking about this very intense and emotional time in their lives with the virtual conference audience. It’s hard not to get emotional seeing their photos of literal writing on the walls that they used to capture moments to remember forever.

The right to get answers about AAV status

Many gene therapies for an array of diseases rely on AAV as the delivery mechanism. Therefore, more and more patients will be wanting to know their AAV immunity status.

When the O’Neills were isolating and awaiting the clinical trial that happened in 2016, no testing options were available outside of research settings.

“We know not every family wants to know their AAV status, which is perfectly fine. But many do want to know, and we need to consider individual family’s preferences, rather than blocking access [to antibody testing and results information],” said Cara O’Neill during their presentation.

Today, families are able to get AAV antibody testing through companies such as Athena Diagnostics, so they can have those answers. However, there are still challenges and barriers.

Protecting the future

“We hope that families in the future aren’t faced with some of those same tough decisions and anxiety around qualifying for a trial like we were,” said Cara O’Neill, a pediatrician and Fellow of the American Academy of Pediatrics, during the presentation. “Families really shouldn’t have to weigh such decisions to remove themselves from daily life, particularly when their child’s life span and quality of life are already so limited by disease.”

She foresees AAV immunity as a significant issue for genetic therapies for all diseases, as a whole.

“AAV immunity is a problem that requires our concentration attention outside of the competitive space for the entire field,” said O’Neill. “Solving this problem is an urgent and ethical imperative.”

The O’Neills understand that on a personal level. While they are extremely grateful for Eliza’s participation in the clinical trial, as it was her only chance. Eliza now has the AAV immunity as a result of the clinical trial therapy. Therefore, she is ineligible for any future AAV-based therapies.

And this is a problem any patient treated with an AAV-based therapy faces.

“While [the clinical trial opportunity] gave us precious hope for a better future [for Eliza], it also shut the door on future therapeutic opportunities … All of these children have been effectively immunized against AAV-9. This as their ‘one shot’,” said O’Neill.

“We know the reality of where our daughter is in this disease, and that does come with some heartbreak. But it’s the reality of where the science was back then and we’re trying to avoid that for future children and future generations,” said Glenn O’Neill.

“Some day soon, we hope a way around these issues of pre-existing AAV immunity become standard for clinical trials.”

“When we talk of hope for families in the future, we don’t want to talk about getting just one chance at it, but options that allow children to get whatever is needed to reach an effective treatment. How could we [the community] strive for anything less?” asked Glenn O’Neill in closing.

Watch the complete presentation on AAV immunity

The O’Neills’ presentation was part of the workshop’s second day. Watch the O’Neills presentation, starting at the 54-minute mark, on the video below.

“We are glad we got to spread more awareness for Sanfilippo syndrome,” said Glenn O’Neill on Facebook. “I hope we represented the topic well for the patient community.”

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