Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses.

Ahmed Morsy,Paul C. Trippier,Angelica V. Carmona

doi:10.3390/molecules26206235

Abstract

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

Highlights

Batten disease, known as neuronal ceroid lipofuscinosis (NCL), is a group of rare pediatric neurodegenerative diseases estimated to affect 1 in 12,500 people [1]
Batten disease is classified into five primary types: (A) Congenital NCL, where babies are born with microcephaly as the disease begins in utero [2]
Another treatment approach used for the NCLs is an adeno-associated virus (AAV)mediated gene therapy

Summary

Introduction

Known as neuronal ceroid lipofuscinosis (NCL), is a group of rare pediatric neurodegenerative diseases estimated to affect 1 in 12,500 people [1]. Predicted transmembrane transporter function plays a role in preventing neuronal loss, robust accumulation of lipofuscin, reactive gliosis, and degeneration and storage accumulation in the retina [24]. Loss of lysosomal cysteine protease activity leads to deterioration of motor function and reduced brain function [31]

Approved Therapies and Ongoing Drug Discovery Efforts for the NCLs

NCL Cellular Models

Summary

Conclusions