I awoke on Monday morning to the sad news that Max Randell had passed away on April 18. He would have been 23 on October 9.

Maxie wasnt expected to live past the age of 8, or even much past toddlerhood, according to some doctors. But gene therapy, and his incredible family, had something to say about that. COVID-19 didnt claim him his body just tired of fighting.

Max Randells legacy is one of hope, to the rare disease community whose family members step up to participate in the clinical trials that lead to treatments. In this time of the pandemic, attention has, understandably, turned somewhat away from the many people who live with medical limitations all the time. Ill explore that story next week.

A Devastating Diagnosis

Max was diagnosed at 4 months of age with Canavan disease, an inherited neuromuscular disease that never touched his mind nor his ability to communicate with his eyes, even though his body increasingly limited what he could do. Fewer than a thousand people in the US have the condition.

Canavan disease is an enzyme deficiency that melts away the myelin that insulates brain neurons. Gene therapy provides working copies of the affected gene, ASPA.

Babies with Canavan disease are limp and listless. Most never speak, walk, or even turn over. Yet their facial expressions and responses indicate an uncanny awareness. A child laughs when his dad makes a fart-like noise; a little girl flutters her fingers as if they are on a keyboard when a friend plays piano. Theyre smart.

Today, with excellent speech, occupational, and physical therapy and earlier diagnosis, people with Canavan disease can live into their teens or twenties. Those with mild mutations live even longer.

Maxs passing is a tragedy, but he taught researchers about gene therapy to the brain. And that may help others.

Gene Therapy for Canavan

Max had his first gene therapy at 11 months of age and a second a few years later, after slight backsliding when clinical trials halted in the wake of the death of Jesse Gelsingerin a gene therapy trial for a different disease.

Ive written about Maxs journey through many editions of my human genetics textbook, in my book ongene therapy, and in several DNA Science posts, listed at the end.

Ive had the honor to attend two of Maxs birthday parties, which celebrate Canavan kids and the organization that his family founded, Canavan Research Illinois. At one party I brought along birthday cards that students whod read my gene therapy book made for him. And his grandma Peggy, who emailed me of his passing this past Monday, showed me how Max communicated with eyeblinks of differing duration and direction.

Heres what his mom Ilyce wrote about one yearly gathering:

This year will be the 20th Annual Canavan Charity Ball. Each year as I plan this event Im faced with the undeniable reality that theres a chance Maxie wont be here by the time the day rolls around. With each passing year this fear grows stronger and it becomes increasingly difficult to put into print that our annual event is in honor of Maxies birthday. Ive been talking to Maxie a lot lately about his life. He feels happy, strong, loved, content, productive, and fulfilled and he is looking forward to his upcoming 21st birthday. Im excited to celebrate this incredible milestone.

Maxs parents and brother Alex have had the unusual experience of time, of being able to watch their loved one as the years unfolded following gene therapy. They were able to see more subtle improvements than can the parents whose children have more recently had gene therapy to treat a brain disease. Parents watch and wait and hope that language will return, or that a child will become more mobile or less hyperactive, depending on the treated condition. The changes may be subtle, or slow, or restricted and thats what Max taught the world.

For him, the viruses that ferried the healing genes into his brain seem to have gathered at his visual system. His parents noticed improvements in the short term, just before his first birthday, as well as long term.

Within two to three weeks, he started tracking with his eyes, and he got glasses. He became more verbal and his motor skills improved. His vision is still so good that his ophthalmologist only sees him once a year, like any other kid with glasses. She calls him Miracle Max, Ilyce told me in 2010.

In 2016 I heard from Ilyce again:

I wanted to give you an update on Maxie. Hes going to be 19 on October 9th. He graduated from high school in June and is beginning a work program on Monday. Its been very exciting to watch him grow into a young man!

Max had an appointment with his ophthalmologist this week and his vision continues to improve. His doctor said that the gene is still active in his brain because his optic nerve shows absolutely no signs of degeneration and looks the same each year. I wish we could have been able to express the gene throughout more of his brain, but I am grateful for the treatments because of the progress hes made.

Even though gene therapy wasnt a cure for Max, the things we are experiencing definitely give me a lot of hope that once the delivery system is perfected, I can see a potential cure for Canavan disease in the future. Just knowing that the gene is still there 15 years later gives me confidence that a one-time gene transfer would actually work!

Maxs gene therapy circa 2002 targeted less than 1% of brain cells, with fewer viral vectors than are used to deliver healing genes in todays clinical trials. But it looks like some of the vectors may have made their way beyond the optic nerves, judging by the interest in math he had in high school and his critical thinking skills.

A Choice of Gene-Based Therapies

When the Randell family decided to pursue gene therapy, it was pretty much the only game in town. Thats changed.

Only two gene therapies have been approvedin the U.S. But a search at clinicaltrials.gov yielded 602 entriesdeploying the technology. The list still rounds up the usual suspects of years past mostly immune deficiencies, eye disorders, or blood conditions, with a few inborn errors of metabolism.

But one clinical trial mentions the gene-editing tool CRISPR, which can replace a mutant gene, not just add working copies as classical gene therapy does. TheCRISPRtrial is an experiment on stem cells removed from patients with Kabuki syndrome, which affects many body systems.

Spinal muscular atrophy now has two FDA-approved treatments, one an antisense therapy (Spinraza) that silences a mutation and the other (Zolgensma) a gene therapy that infuses copies of the functioning gene. Without treatment, the destruction of motor neurons in the spinal cord is usually lethal by age two.

In 2018, FDA approved the first drug based on RNA interference (RNAi), yet another biotechnology. It silences gene expression, which is at the RNA rather than the DNA level of the other approaches. Onpattro treats the tingling, tickling, and burning sensations from the rare condition hereditary transthyretin-mediated amyloidosis.

When I wrote my book on gene therapy in 2012, the technology was pretty much the only choice of research to pursue besides protein-based therapies like enzyme replacement. Now families raising funds for treatments for single-gene diseases can add antisense, RNAi, and CRISPR gene editing to the list of possibilities.

In any battle, a diversity of weapons ups the odds of defeating the enemy.

RIP Max Randell.

DNA Science posts:

Fighting Canavan: Honoring Rare Disease Week

A Brothers Love Fights Genetic Disease

Gene Therapy for Canavan Disease: Maxs Story

Celebrating the Moms of Gene Therapy

To support research:Canavan Research Illinois

Go here to see the original:

A Tribute to Max Randell, Gene Therapy Pioneer - PLoS Blogs