Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2

Abstract

Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human CLN2, in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort (P < 0.04) and European natural history cohort (P < 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy.

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

“…ERT introduces purified recombinant enzymes via intravenous, intracerebroventricular or intrathecal injection into the subarachnoid space to bypass the blood-brain barrier [4,11,12]. There have been encouraging reports of treatments in CLN2 slowing decline [16][17][18]. ERT administration does not alter the progressive retinal degeneration [18], probably because of the spectrum of the eye's immune privilege and blood-retina CNS barrier [19], but intravitreal administration of rhTPP1 has slowed retinal degeneration in four TPP1-null dogs [20].…”

Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice

“…In our intracerebral AAVrh.10 gene therapy trial (NCT01801709), despite long-lasting restoration of ARSA activity in the CSF, we failed to demonstrate any clinical effect, even in pre-symptomatic patients with LI-MLD (Sevin et al, 2018). Inconstant results were observed in clinical trials using intracerebral GT for other lysosomal diseases (MPSIIIA, MPSIIIB, LINCL) (Tardieu et al, 2014(Tardieu et al, , 2017Sondhi et al, 2020). New routes of administration (intra-CSF, intravenous) are currently under clinical evaluation, most of them using AAV9 vector.…”

Missense Variation in <em>TPP1</em> Gene causes Neuronal Ceroid Lipofuscinosis Type 2 in a Family from Jammu and Kashmir-India

“…The clinical management of CLN2 is complex, which primarily encompasses supportive and palliative care, pharmacological treatment of symptoms presented in CLN2 paediatric cases, enzyme replacement therapy (ERT) and gene therapy [20][21][22][23]. Antiepileptic drugs, including benzodiazepines (clobazam/clonazepam, lamotrigine, levetiracetum and valproate, are the common first-line therapeutics used for the management of epileptic as well as non-epileptic seizures and myoclonus [22].…”

“…It was disheartening to find out upon genetic screening of the family that the younger, year old asymptomatic kid is also harbouring the same variation in a homozygous manner. With new developments in place for the pharmacological treatment of symptoms presented in CLN2 paediatric cases as well as enzyme replacement therapy (ERT) and gene therapy [20][21][22][23], it is anticipated if interventions are provided at this juncture too, may help the family extensively and the affected kids (in particular) in leading a better life.…”