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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
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.
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
Batten disease: an expert update on agents in preclinical and clinical trials
Published in Expert Opinion on Investigational Drugs, 2020
Margaux C. Masten, Jonathan W. Mink, Erika F. Augustine
NCL forms differ by the causative gene, gene product, and affected the biologic process. Some of the affected proteins are soluble enzymes and others are membrane-bound proteins. There are no blood biomarkers that have been shown to correlate with disease progression in any form of NCL. Successful disease-modifying therapy (DMT) approaches may differ based on the location and function of the individual protein. For example, CLN2 disease is caused by a mutation in the gene that codes for tripeptidyl peptidase 1 (TPP1), a soluble lysosomal enzyme, which can be treated with enzyme replacement therapy (ERT). By contrast, CLN3 disease is caused by a mutation that affects a transmembrane protein and thus is not a candidate for ERT. Potential approaches to disease modification include, but are not limited to, small-molecule drugs, large-molecule drugs, genetic medicines, and combination therapies. There is currently one disease-modifying ERT (cerliponase alfa) that has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of CLN2 disease. Several other potential disease-modifying therapies have been tested in small clinical studies (Table 1), but none of these has led to FDA or EMA approval. The focus of this editorial is on the current therapeutic pipeline for DMTs in the NCLs, including promising pre-clinical studies and planned and ongoing clinical trials. For a more extensive review, see [2].