One of the highlights of our job is watching orphan drug therapies being advanced thanks to the efforts of advocacy groups. Case in point – gene therapy research at Children’s Hospital of Philadelphia (CHOP) with funding in part by the Batten Disease Support and Research Association (BDSRA
), Jasper Against Batten Fund at Partnership for Cures, and Blake’s Purpose Foundation
(along with NIH and CHOP funding), was recently published in Science Translational Medicine
showing the viability of gene therapy in an animal model for Batten disease.
Batten disease is a lysosomal storage disorder in which the person lacks a properly functioning enzyme, tripeptidyl peptidase 1 (TPP1)—an enzyme that normally allows brain cells to recycle cellular waste. Children with Batten disease due to TPP1 deficiency, also known as CLN2 disease, have multiple neurological impairments, including severe motor, cognitive, auditory, and visual impairments. Symptoms and seizures usually appear between ages two and four, and the disease progresses, with most children dying by age 10.
There are currently no treatments available for Batten disease and while most lysosomal storage disorders benefit for enzyme replacement therapies, the blood brain barrier makes that type of therapy problematic. Gene therapy, on the other hand, is ideal for conditions such as Batten disease.
The researchers at CHOP tested a gene therapy in an animal model for Batten disease.
In the study, recombinant adeno-associated virus (rAAV) expressing the canine form of TPP1 (caTPP1) was infused into ventricles of dogs lacking caTPP1. The infusion allows for gene transfer to the cells lining the ventricles, the ependymal cells, for expression and subsequent secretion of the TTPI into the cerebrospinal fluid. Because the cerebrospinal fluid bathes the brain, the enzyme could ultimately move from the fluid filled spaces to the brain cells themselves for uptake and correction of cell pathologies.
The TPP1-null dogs were generated from heterozygous breeding. During the course of the study, animal were given the gene therapy or were untreated and compared to similar dogs that had functioning TTP1.
In untreated TPP-null dogs, clinical signs of ‘Batten disease’ begin around 5 months of age and most dogs will require euthanasia by 11 or 12 months. An early symptom in these dogs is impaired proprioceptive responses in the hindlimbs. In dogs given the gene therapy, this early symptom was delayed an average of 4.5 months. Other common symptoms in the dog model such as nystagmus and menace response deficits did not develop until later, or did not appear, in animals given the gene therapy.
Cognitive abilities and overall lifespan were also improved with the gene therapy. While gene therapy did not cure the animals, it did prolong their life and improve its quality. In untreated animals, humane euthanasia occurred at around 10 months whereas in the dogs given gene therapy, they lived to be an average of 17.5 months.
In a press release,
Beverly L. Davidson, PhD, director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP said, "One treatment of gene therapy gave these dogs a remarkable improvement in their quality of life." Dr Davidson added, "If the outcome is equally profound in children with the same enzyme deficiency, this would represent a great benefit for affected children and their families." In addition to improvements in motor control and cognition, it could reduce patient risk by avoiding repeated access to the brain for life-long enzyme infusions or the need for implanted enzyme-delivery devices.
Katz ML, Tecedor L, Chen Y, et al. AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease.Science Translational Medicine.
2015;7(313): DOI: 10.1126/scitranslmed.aac6191