A Reason to Celebrate: Children with a Severe Neurological Disorder Improve After Gene Replacement

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July 6 was my birthday, which means business as usual. I like it that way -- the fewer interruptions to my workday the better. At 1 p.m. I was hosting a meeting with the executive committee of the Cure Rett Working Group (CRWG), a year-long effort that RSRT spearheads to aid biopharma pursuing or exploring Rett syndrome programs. During the call I received an email alert about a study that caught my attention. I couldn’t resist taking a quick look, and as I did my heart skipped a beat. It took all of my will power to not interrupt the meeting with the news. I waited until the end and then put a link to the news story in the chat.

Fyodor Urnov, PhD, a gene editing expert whom I have known for over two decades and who is co-organizing CRWG with me, quickly skimmed the article and started uttering, “Wow…wow!”

During the next day or two I forwarded the publication to a number of biopharma contacts pursuing Rett programs, but news of the article had already spread like wildfire.

Why all the fuss?

Krystof Bankiewicz MD, PhD, professor of neurological surgery at Ohio State College of Medicine, conducted a small gene replacement clinical trial in seven children aged 4 to 9 years old and published his study results in the journal Nature Communications. The study tested a gene replacement for a disorder called Aromatic L-amino acid decarboxylase (AADC) deficiency. Caused by deficient synthesis of dopamine and serotonin, it causes severe developmental disability from infancy and presents with lifelong motor, behavioral, autonomic symptoms, sleep issues, and more.

Using an AAV2 vector, the AADC gene was delivered to two specific parts of the brain that are critical in this particular disease. The gene replacement therapy was safe and well tolerated and, importantly, the children started improving. Within a year, six of the seven children gained normal head control, and four of the seven could sit independently; oculogyric crisis disappeared in six of the seven children. By 18 months, two children could walk with support. With continued intense rehabilitation it is my fervent hope that these children will continue to improve.

Every parent of a child with Rett is familiar with the landmark reversal experiments conducted by Adrian Bird in the Rett mouse model. The question of how well those dramatic results in mice will translate to people is one that comes up often in my interactions with scientists and biopharma.

No one has any doubts that at some point we will have a cure to administer to future infants diagnosed with Rett via newborn screening, which will stop Rett symptoms from ever developing. But is it possible for our children, the ones who are here now, who already have symptoms, to significantly improve? The dogma in neuroscience is that once critical developmental windows have closed there is little chance to recoup milestones.

The AADC deficiency clinical trial results argue against that dogmatic thinking. As the first author of the paper, Toni Pearson, explains, “It’s been eye-opening for me to see that there’s not a critical period of time at which development has to take place and if it doesn’t, that capacity vanishes. We still think that the earlier this could be delivered, the better the potential for benefit. But I think we’re discovering what the window of plasticity is for still making progress.”

Additional encouraging data comes from a clinical trial in Angelman Syndrome using a therapeutic known as an antisense oligonucleotide (ASO). Five patients between the ages of 5 and 15 were treated, though the dosing is being refined to reduce side effects before additional patients enroll. Rapid improvements were seen in a variety of areas including communication, sleep, behavior, fine and gross motor skills.

These incredible improvements for AADC deficiency and Angelman Syndrome don’t guarantee that we will see improvements for Rett, but they do suggest that the window for postnatal correction of a genetic mutation might be much bigger than previously thought. Their success should give us all a remarkable amount of hope for what is possible for Rett syndrome.

This is exciting. It’s motivating. It’s worth celebrating. Making these outcomes a possibility for my daughter and all those with Rett is our goal at RSRT.

The AADC deficiency results were some of the best news I had read in a long while. Turns out my birthday was more than business as usual.