Clinical Trial Set to Start for CLN1 Batten Disease

On May 21, Abeona Therapeutics announced the go-ahead from the Food and Drug Administration (FDA) for a clinical trial to test a gene therapy for a form of Batten disease called CLN1 disease, aka infantile neuronal ceroid lipofuscinosis. The King family and their organization Taylor’s Tale has supported the research that made the clinical trial possible since their beloved Taylor was diagnosed at age 7 in 2006.

The eight forms of Batten disease are ultrarare – together they account for only 1 in 100,000 individuals. Each is caused by mutation in a different gene, but all cause neurodegeneration. The conditions were originally named for what was thought to be the typical age of onset, before much was known about the genetics or the natural histories. CLN1 is now recognized to manifest in infancy, late infancy, and in children (juvenile), and Taylor had the juvenile form.

CLN1 is the classic “infantile” form. But Taylor King was no longer an infant when she experienced the first subtle sign, a new difficulty with numbers in the first grade. Taylor had taught herself to read at age three.

“There were signs of the secret hiding in Taylor’s genes even then, but they were too complex and too twisted for any of us to understand,” wrote her sister Laura in her book Run to the Light , which I reviewed here.

Taylor’s Tale

Taylor’s vision changed gradually. When she froze on a shaded, narrow stairway leading out of a restaurant at the state fair when she was 7, the family realized her black and white vision was failing. Within a few weeks, the little girl began moving her head to capture images on a screen or see who was talking – her central vision lost.

For a time, retinitis pigmentosa led the list of possible diagnoses. Then the combination of declining vision, “nonverbal learning disorder,” and poor math skills alerted a physician, who sent Taylor for genetic testing. The diagnosis of Batten disease came as a shock.

Wrote Laura, “I typed the unfamiliar phrase into Google with trembling fingers and crumpled into my desk chair as I read the results. Words and phrases shot off the screen and straight into my vulnerable flesh like icy daggers, each one more awful than the last: Rare. Inherited. Progressive. Seizures. Motor deterioration. Cognitive deterioration. Blindness. No treatment. No cure. Early death. We found out my little sister was dying on a parched morning in the summer of 2006, just a few weeks shy of her eighth birthday and a month after my wedding.” Laura spent a lot of time with her much-younger sister during the preschool years.

A more tragic juxtaposition lay ahead. Last September, 2018, as Laura was in labor for her first child, Taylor lay downstairs on the hospice floor at the same hospital. Jack came into the world on September 20; his 20-year-old aunt passed away six days later.

Laura King Edwards and Sharon King formed Taylor’s Tale just a few months after the shattering diagnosis, when it was still difficult to imagine what, exactly, was to come.

Taylor worked hard. “She learned braille. She memorized the halls of her school. She ran two 5K races with a guide. She joined her friends in school talent shows. But Batten disease, over more than a decade, robbed Taylor of her vision, her speech, her mobility, and her ability to swallow,” mother and sister wrote on the website.

The goal of Taylor’s Tale was to fight back, just as Taylor had. After much research, gene therapy emerged as the way to go, and I met Laura and Sharon after they found my book about gene therapy.

In 2013, the organization decided to support the work of Steve Gray, PhD, then at the University of North Carolina and later at the University of Texas Southwestern Medical Center. Taylor’s Tale also pushed for passage of 2015’s Taylor’s Law, establishing the nation’s first rare disease advisory council, in North Carolina. The state has a million rare disease patients.

Taylor’s Tale continued it’s efforts even after it became clear that Taylor didn’t have much time left. Now Abeona Therapeutics is taking Dr. Gray’s preclinical work into the clinic.

The gene therapy, called ABO-202 for now, is unusual in that it will be sent into the spinal cord and into the bloodstream, targeting the central nervous system and peripheral nervous system, respectively. In mice “the combined intravenous and intrathecal administration approach showed additional benefits compared to a single route of delivery, providing a new treatment paradigm for patients with devastating neurological diseases,” said Dr. Gray.  It extended life and restored neural function. The one-time treatment will be delivered aboard the well-studied AAV9 viral vector.

The Road to Gene Therapy

Many milestones mark the journey to gene therapy.

The first step is discovery of the target, the gene in which mutations cause a clinically recognized syndrome.

CLN1 arises from mutation in the PPT1 gene. It encodes an enzyme (palmitoyl-protein thioesterase-1) that functions in the lysosomes, the sacs inside cells where dozens of vital enzymes break down specific biochemicals for recycling. Inability of an enzyme to function in this cellular garbage dump results in a lysosomal storage disease.

Most children with CLN1 don’t live past age 5 because their cells don’t make any PPT1, but the fact that Taylor’s cells made about 2 percent of the normal output of the enzyme likely enabled her to live to age 20. “It delayed the buildup of gunk in her cells. She was rare among the rare,” Laura said. Still, the lysosomes in Taylor’s neurons became inflamed and degenerated into a long, slow decline.

Once a mutation is identified and how it derails specific types of cells discovered, designing a gene therapy entails engineering a vector to deliver a working copy of the implicated gene, followed by testing in animal models of the human disease and/or in human cells. These are preclinical tests, and they often continue even after gene therapy trials begin. One reason – once a gene therapy (or any other) works and extends life significantly, new symptoms can appear.

The CLN1 community is now at the starting gate for testing the gene therapy in children. The phase 1/2 clinical trial will evaluate safety and, if all goes well, efficacy. Abeona will announce the starting date for the trials later this year, which will be conducted at the University of Rochester Medical Center in the U.S. and the University of Hamburg-Eppendorf in Germany and possibly elsewhere.

“It’s an incredible milestone for our organization and CLN1 patients and families, as well as many others whose condition could potentially be treated with gene therapy. This is why we founded Taylor’s Tale – to spearhead and enable the development of a viable treatment for CLN1 disease. So many called it an impossible mission, but we believed enough to try, even after it became clear Taylor wouldn’t survive long enough to benefit. We’re grateful to Steve Gray, our partner and friend for the past six years, to Ale Rozenberg, who played an instrumental role in moving Steve’s work forward, and to the entire team at Abeona for all they’ve done to guide it to the clinical stage,” said Laura.

Conclude Laura and Sharon on the Taylor’s Tale website, “We may have lost the battle for Taylor, but we are winning the war for so many others. This is her legacy, and ours.”