Batten Disease Treatment

Enzyme therapy now under trial for preventing blindness in patients.

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Enzyme therapy now under trial for preventing blindness in patients. Roibeárd O’hÉineacháin reports. A compassionate use programme evaluating the safety and efficacy of the intravitreal administration of the recombinant enzyme, cerliponase alfa (Brineura®, BioMarin Pharmaceuticals), in preserving vision in children with CLN2-related late infantile Batten disease is now underway at Great Ormond Street Hospital in London, UK. “This first intravitreal enzyme replacement programme is an exciting opportunity that we hope will preserve both vision and quality of life for children with this devastating disorder,” Mr Robert Henderson, the study’s lead investigator, told EuroTimes. The 18-month programme involves eight CLN2 Batten disease patients aged between five and 10 years. All are undergoing intravitreal injection of Brineura under general anaesthesia in one eye every two months for a minimum of 12 months. The primary endpoint is safety in this first-in-man intravitreal enzyme replacement treatment. The investigators will, additionally, compare the central macula volume derived from Heidelberg Flex OCT measurements taken in the operating room. They will also evaluate visual acuity and electroretinogram preservation. Batten disease is an umbrella term for a group of hereditary neurodegenerative lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCL). The CLN2 type results from autosomal recessive mutations in the gene that codes for Tripeptidylpeptidase 1 (TPP1), a lysosomal protease that breaks down waste products in neuronal lysosomes. The resulting absence of the enzyme allows the waste products to build up in the neurons, ultimately resulting in neuronal apoptosis. The symptoms of CLN2 disease first appear between ages two and four years, commonly with seizures and both motor and cognitive regression. This is followed at around five years of age by progressive visual impairment secondary to a cone-rod retinal degeneration that culminates in total blindness. Children with late infantile Batten disease generally die by 10–12 years of age. ENZYME REPLACEMENT THERAPY Brineura is a recombinant form of the missing TPP1 enzyme and is the first treatment to show efficacy in slowing disease progression in children with CLN2. The enzyme replacement therapy was approved by the FDA on 27 April 2017 and by the UK NHS in 2019, where it is available under a managed access agreement. The current protocol for administering Brineura is through direct intracerebroventricular infusion using a reservoir device implanted under the scalp with a catheter placed into the ventricles. Patients receive the infusions every two weeks. “This approach has proven effective in slowing the pace of developmental decline and, in some children, restoring lost motor skills. It does not, however, prevent blindness, as it is believed the recombinant enzyme does not appear to cross the blood retinal barrier,” Mr Henderson noted. INNOVATIVE INTRAVITREAL APPROACH Intravitreal injection of Brineura has proven effective in preventing retinal degeneration in a study using the canine model of CLN2. In dogs that received periodic intravitreal injections of Brineura in one eye and vehicle in the other, the Brineura-treated eye retained greater retinal function and more normal morphology than the contralateral vehicle-treated eyes, which exhibited the loss of inner retinal neurons and the photoreceptor disorganisation typical of CLN2 disease. Furthermore, the treatment effect from a single injection lasted several months. Inflammation was the only side effect detected and was controllable with topical steroids. “Given the success of treating the dog model, families of patients with the disorder were naturally extremely keen to gain access to an intravitreal treatment for their children. Clinicians at Great Ormond Street applied to the hospital ethics committee for permission to undertake a compassionate use programme, in the absence of any other treatment and considering the rapid deterioration of vision, which was granted,” Mr Henderson said. Residual cerliponase, left in the vial from the ICV infusions, is prepared for intravitreal injection in the hospital’s pharmacy using similar dosages to the dog model (0.2 mg in 0.05 mL). All children receive topical steroids for one month after treatment and undergo monitoring for signs of uveitis at each visit. The Great Ormond Street Hospital compassionate use programme, which started in July 2021, has been made possible thanks to a huge fundraising campaign led by the families of children affected by the disease as well as the Batten Disease Family Association (BDFA), a UK charity that aims to support families, raise awareness, and facilitate research into the various types of Batten disease. Formal drug company-sponsored clinical trials are also underway in Columbus, Ohio, USA, with more planned in Hamburg, Germany. Mr Robert Henderson MD, FRCOphth, is a Consultant Paediatric Ophthalmologist & Vitreoretinal Surgeon, Moorfields Eye Hospital, Great Ormond Street Hospital, London, UK. robert.henderson@gosh.nhs.uk