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Targeted Gene Therapy Aimed at Devastating Childhood Disease

Published on November 12, 2015 in Cornerstone Blog · Last updated 6 months 2 weeks ago


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When something important is missing, we often search for a replacement. After many years of looking, a team of researchers at The Children’s Hospital of Philadelphia and the University of Missouri have found a way to substitute for a missing gene linked to a relentless childhood neurodegenerative disease.

Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL-Batten Disease) is a rare, inherited condition that erodes toddlers’ abilities to walk, talk, think, and see. Their development appears normal until debilitating symptoms and seizures arise between ages 2 to 4 and then gradually worsen until the children succumb to disease, generally by age 10.

LINCL-Batten is caused by mutations in the TPP1 gene, which encodes the lysosomal enzyme TPP1 that every brain cell needs in order to get rid of waste. When TPP1 is deficient, scientists using fluorescent microscopes can see glowing accumulations of storage material in cells, which is a hallmark of LINCL-Batten.

Beverly Davidson, PhD, director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP and her research team have been trying to understand what is going wrong in the absence of these proteins and how they can develop therapies to treat children with LINCL-Batten.

In a new paper published in the journal Science Translational Medicine, they describe a novel approach using canine TPP1 gene transfer to treat dogs who have TPP1 deficiency and manifest the disease in ways comparable to humans. The lead co-authors included Luis Tecedor, PhD, and Yong Hong Chen, PhD, both from CHOP, and Martin Katz, PhD, of the University of Missouri.

During a 30-minute surgical procedure, a surgeon infuses the gene vector into the dog’s brain. The vector delivers its genetic material to a subset of cells that can then secrete the protein into the cerebral spinal fluid bathing the brain. Subsequent long-term and widespread distribution of TPP1 helps to correct the disease in the dog model.

A one-time infusion resulted in a “remarkable clinical benefit,” the study authors wrote. The treated dogs showed delays in onset of clinical signs and disease progression, protection from cognitive decline, and extension of lifespan.

“With gene therapy, we not only change when those symptoms occur, but we also spread them out,” Dr. Davidson said. “We give the dogs a profound improvement in their quality of life. It is really remarkable.”

Dr. Davidson envisions a similar short procedure could be used to target gene therapy in the brains of children with LINCL-Batten. Early diagnosis will be crucial so that the intervention could preserve as much of their functions as possible and prolong the onset of declines. It is unknown if TPP1 replacement could potentially alleviate any brain damage that already has occurred.

A “one and done” infusion would be a valuable alternative to another experimental therapy that is available called TPP1 enzyme replacement therapy (ERT). While the two approaches share the same basic concept, ERT does not rely on delivery of the TPP1 gene. Instead, it requires children to make biweekly visits to the intensive care unit to receive infusions of TPP1 through an indwelling device.

Dr. Davidson anticipates her lab’s gene therapy research will be ready to translate to a human clinical trial soon. “If the outcome in children with TPP1 deficiency is as profound as in the canine model, we would expect an enormous benefit to the quality of life of the affected children, and also their families,” Dr. Davidson said.

The National Institutes of Health, the Batten Disease Support and Research Association, Blake’s Purpose Foundation, the Roy J. Carver Trust, and the Children’s Hospital of Philadelphia Research Institute supported the canine investigations. The research team at the University of Missouri contributed to the study as well and provided exemplary collaboration in providing for the care and health of the dog colony.