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External Control Using RWE and Historical Data in Clinical Development
Published in Harry Yang, Binbing Yu, Real-World Evidence in Drug Development and Evaluation, 2021
Qing Li, Guang Chen, Jianchang Lin, Andy Chi, Simon Davies
Batten disease, which is also called neuronal ceroid lipofuscinoses (NCLs), is a family of rare, fatal, inherited disorders of the nervous system. It is estimated that 2–4 births per 100,000 in the United States are affected by Batten disease, which is considered as a rare disease. Batten disease was named after British pediatrician Frederick Batten, who first described the disease in 1903; however, there were no approved drugs until recently. In April 2017, the FDA approved Brineura® (cerliponase alfa), which was developed by BioMarin Pharmaceutical, Inc. as a treatment for a specific form of Batten disease (FDA 2017c). It is the first FDA-approved treatment to slow the loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. The BLA of Brineura® received priority review and breakthrough therapy designation.
Considerations and Bayesian Applications in Pharmaceutical Development for Rare Diseases
Published in Mani Lakshminarayanan, Fanni Natanegara, Bayesian Applications in Pharmaceutical Development, 2019
Batten disease is a fatal rare disease of the nervous system that typically has onset of symptoms in childhood and causes worsening problems with vision, movement, and thinking ability.39,40 It is usually referring to a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), to which CLN2 disease belong. CLN2 disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency. In the late infantile form of the CLN2 disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy), and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease collectively is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.41
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Three genes encoding lysosomal enzymes and five encoding lysosomal transporters have been delineated. CLN1 and CLN2 encode palmitoyl protein thioesterase and tripeptidyl peptidase type 1, respectively and their activity can be measured on white cell assay. However, if the history is strongly suggestive but enzymology is negative, electron microscopy of leukocytes/fibroblasts may be performed, searching for the presence of characteristic inclusions. Gene sequencing is needed for subtyping. While there is generally good genotype–phenotype correlation there is also genetic heterogeneity whereby, for instance, different mutations in CLN1 can cause infantile or adult onset disease.
Preclinical and clinical developments in enzyme-loaded red blood cells: an update
Published in Expert Opinion on Drug Delivery, 2023
Marzia Bianchi, Luigia Rossi, Francesca Pierigè, Sara Biagiotti, Alessandro Bregalda, Filippo Tasini, Mauro Magnani
Regarding enzyme replacement therapy approaches, several lines of evidence are accumulating in favor of loading therapeutic enzymatic proteins in EVs of different origin. For example, Liu et al. loaded catalase and glucose oxidase into macrophage-derived EVs for targeted photodynamic therapy in cancer [21]. Two further applications are found in the field of lysosomal storage disorders and are reported below. Do et al. loaded the enzyme β-glucocerebrosidase into engineered exosomes from different cell types for the treatment of the lysosomal Gaucher’s disease. They demonstrated that the enzyme was efficiently targeted to the endocytic compartments and exhibited significant activity into the recipient cell [126]. Haney and coworkers produced macrophage-derived EVs for brain delivery of the soluble lysosomal enzyme tripeptidyl peptidase-1, TPP1, to treat Batten disease [127]. Importantly, both groups transfected the ‘mother’ cells with enzyme-coding DNA and then isolated the enzyme-containing EVs produced by the cells.
Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies
Published in Expert Review of Neurotherapeutics, 2021
Maria Mazurkiewicz-Bełdzińska, Mireia del Toro, Göknur Haliloğlu, Hidde H. Huidekoper, Ružica Kravljanac, Chris Mühlhausen, Brian Nauheimer Andersen, Igor Prpić, Pasquale Striano, Stéphane Auvin
CLN2 disease is a lysosomal storage disorder in the neuronal ceroid lipofuscinosis (NCL) family caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1), resulting from mutations in the TPP1 gene [2,28]. CLN2 disease is rare, affecting fewer than 1 in 100,000 live births in most studied populations [1,2,6,29–31]. CLN2 disease typically presents with seizures between the age of 2 and 4 years, with language delays increasingly reported as a preceding symptom [1,3–5,7,32]. In an observational cohort study, seizures and language deficits were one of the presenting symptoms in 70% of patients and 57% of patients, respectively [7]. Other symptoms reported at presentation included developmental delay, motor dysfunction, ataxia, behavioral abnormalities, and dementia [1,7,32,33].
Ocular Manifestations of Neuronal Ceroid Lipofuscinoses
Published in Seminars in Ophthalmology, 2021
Rohan Bir Singh, Prakash Gupta, Akash Kartik, Naba Farooqui, Sachi Singhal, Sukhman Shergill, Kanwar Partap Singh, Aniruddha Agarwal
CLN2 encodes for tripeptidyl-peptidase 1 (TPP1), a lysosomal serine protease.45–47CLN-2 is an autosomal recessive disease which occurs as a consequence of loss of function in the TPP1/CLN2 gene on chromosome 11p15 which leads to deficient activity of TPP1.48 Though the exact pathophysiology is yet to be elucidated, animal studies have shown that insufficient TPP1 activity leads to intralysosomal accumulation of autofluorescent storage material, which causes pronounced neurodegeneration within the thalamocortical system, cerebellum and retinal pathway along with progressive reactive astrocytosis in the motor cortex, hippocampus, striatum, and cerebellum.49,50 Retinal degeneration begins at the photoreceptor and outer retinal levels and advances from the macular area to the periphery, eventually leading to complete atrophy of retina and blindness. Curvilinear deposits in the lysosomes on electron microscopy is characteristic of CLN-2.14,40 Clinical manifestations of CLN-2 usually starts with language delay and epilepsy around 2–3 years of age with progression to ataxia and global developmental delay by 5 years of age.42,43,51,52