Alternating Hemiplegia of Childhood, or AHC, was largely thought to be incurable and without treatment options. This was devastating news to the family of four-year-old Henry Saladino, who suffers from seizures, paralysis, apnea and developmental delays due to the rare, life-threatening neurological disease.
That is, until Dr. Timothy Yu and his team of neurologists at Boston Children’s Hospital joined the conversation. Since 2017, Dr. Yu’s lab has developed precision drugs called antisense oligonucleotides, or ASOs, for four previously untreated diseases. Now, his lab is working on a fifth made specifically for Henry.
Dr. Timothy Yu, neurogeneticist and principal investigator of the Yu Lab at Boston Children’s Hospital, joined GBH’s All Things Considered host Arun Rath to shed some light on his medical advancements. What follows is a lightly edited transcript of their conversation.
Arun Rath: Before we get into the specific treatment for Henry, help us get a general understanding of ASO development overall. I’ve heard you liken it to Lego blocks in the past.
Dr. Timothy Yu: Yes, antisense oligonucleotides are like Lego blocks. They are short snippets of synthetic pieces of the human genome, so to speak, either DNA or RNA-like molecules that normally encode all of the information necessary to construct the human body. Here, we’re taking short snippets of these Lego building blocks to use as drugs to try and treat individuals who are unfortunate to have genetic conditions like Henry’s.
Rath: Tell us a bit about the success with previous diseases that previously had no treatment. What were they, and how were they similar to each other?
Dr. Yu: Antisense oligonucleotides as a strategy for combating disease have been in scientists’ and doctors’ minds and eyes for about 30 years. I would say the first really runaway success of an antisense oligonucleotide drug for a human condition was in 2017, with really remarkable results of an ASO drug for a childhood condition called spinal muscular atrophy. This is a childhood condition where infants are born weak and grow progressively weaker due to a genetic defect that leads to neurons in a part of their spinal cord to eventually lose function and then die.
A remarkable drug using this ASO technology was conceived of that could correct gene expression of the faulty gene and led to kids with this condition having really remarkable benefits. These children who were born weak were able to grow stronger and evade all of these very serious medical complications that they would normally have, as long as they received the drug.
That drug, Spinraza, approved by the FDA in 2017, has really paved a path for using this type of Lego building block technology to make other drugs for other conditions, especially ones affecting the brain and the eye that were previously considered untreatable.
Rath: Tell us a bit more about Henry’s condition. What about Henry’s disease is different from previous work?
Dr. Yu: Henry’s condition—as you said, Alternating Hemiplegia of Childhood—is a disorder in which mutations in a critical energy pump that is required for the brain to function properly cause neurons in the brain to intermittently lose the ability to function.
As a result, children with this condition have altered brain maturation and brain development. Their normal ability to achieve milestones like walking, running, learning to speak and learning social skills is, unfortunately, impaired.
On top of that, there are symptoms that they exhibit where parts of their brain temporarily stop working. It results in a very curious but very, very serious constellation of symptoms, where they can experience episodes of weakness or paralysis that might affect one side of the body at a time—hence the medical term “hemiplegia”—or even both sides of the body at once.
They can also have intermittent abnormal movements of the eyes, muscle stiffness and abnormal tone in their muscles that come and go in an arm, leg or torso. They can also have seizures.
Rath: When you’re developing ASOs for individual diseases, are they each their own individual mystery, or does the development of one ASO help lead to another one?
Dr. Yu: That’s an excellent question. This space that we’ve been working in over the last five years is really a frontier in medicine. It’s only in the last several years—the last five to 10 years—that the causes of some of these conditions, like Henry’s, are becoming known. It’s only in the last very few years—five years or less—that we’ve had tools like ASOs available that allow us to begin to try to treat them as such.
As a neurologist and a scientist, it’s a really special privilege to work in these early days because every effort on behalf of a disease like Henry’s has the opportunity to teach us about how well this method might work. Lessons learned from trying to develop this type of Lego building block — an ASO drug for AHC — have payoffs for other strategies to treat AHC, such as with other types of gene therapy. They also have payoffs for using ASOs to treat all sorts of other conditions beyond Henry’s and beyond AHC.
Rath: It kind of makes your head spin to think about this because what you’re doing as a neurogeneticist isn’t a new job, and the kind of things you’re doing was science fiction up until just a few years ago. Can you give us a sense of the scale of this? It seems like an amazing new age, like we’re getting these genetic treatments that we only ever heard about in science fiction.
Dr. Yu: It really is, with the necessary caveat, of course, that we’re on the cusp of really amazing things, but we’re not quite there yet.
I’ll share a little story. This work that we’re doing right now to try and develop some of the first treatments for these pediatric neurology conditions has the potential to be a huge game changer. My mother, actually, was a hematologist oncologist. I remember growing up, I used to go attend her clinic at [University of California] San Diego, where she would treat young kids around my age who had a variety of different sorts of childhood cancers.
I remember that she told me—after one visit to the clinic and seeing lots of kids in hospital gowns with IV pulls, many of them missing their hair because of chemotherapy—that, sadly, about half of the children she treated with these most serious conditions ultimately didn’t make it.
I remember asking her, “Mom, why do you do this work? Isn’t it depressing to work with a population where you lose half of your patients?” She turned to me and said, “Well, the reason I do this is because when I started this work two decades ago, 90% of them passed away, and now we’re able to save half of them.”
That story reminds me a lot of where we hope to be in our field in, hopefully, fewer than 20 years, but it feels like that change is possible now with these tools. We’re just at the very beginning where these conditions, many of which are very, very serious and can lead to death, we now have options available to us. With effort, lots of hard work and with really brave families like Henry’s and others with his condition as our partners, I think we have a chance to begin to bend that curve.