Fingolimod and Teriflunomide Attenuate Neurodegeneration in Mouse Models of Neuronal Ceroid Lipofuscinosis

Molecular Therapy : the Journal of the American Society of Gene Therapy
Janos GrohRudolf Martini

Abstract

CLN diseases are rare lysosomal storage diseases characterized by progressive axonal degeneration and neuron loss in the CNS, manifesting in disability, blindness, and premature death. We have previously demonstrated that, in animal models of infantile and juvenile forms of CLN disease (CLN1 and CLN3, respectively), secondary neuroinflammation in the CNS substantially amplifies neural damage, opening the possibility that immunomodulatory treatment might improve disease outcome. First, we recapitulated the inflammatory phenotype, originally seen in mice in autopsies of CLN patients. We then treated mouse models of CLN1 and CLN3 disease with the clinically approved immunomodulatory compounds fingolimod (0.5 mg/kg/day) and teriflunomide (10 mg/kg/day) by consistent supply in the drinking water for 5 months. The treatment was well tolerated and reduced T cell numbers and microgliosis in the CNS of both models. Moreover, axonal damage, neuron loss, retinal thinning, and brain atrophy were substantially attenuated in both models, along with reduced frequency of myoclonic jerks in Ppt1-/- mice. Based on these findings, and because side effects were not detected, we suggest that clinically approved immune modulators such as fingolimod ...Continue Reading

Citations

May 18, 2018·Human Molecular Genetics·Laura D WeinstockYulia Grishchuk
Mar 11, 2020·Expert Review of Neurotherapeutics·Antonella RivaPasquale Striano
Sep 18, 2020·Expert Reviews in Molecular Medicine·Pascual Sanz, José M Serratosa
Jul 23, 2020·Drugs in R&D·Pablo BascuñanaJens Pahnke
Nov 18, 2018·Documenta Ophthalmologica. Advances in Ophthalmology·Fred K ChenSamuel McLenachan
Jun 18, 2020·International Journal of Molecular Sciences·Kim M A De Kleijn, Gerard J M Martens
Sep 18, 2020·Scientific Reports·Hemanth R NelvagalJonathan D Cooper
Mar 17, 2019·CNS Drugs·Alfried KohlschütterStephan Storch
Feb 21, 2019·Nature Reviews. Neurology·Tyler B JohnsonJill M Weimer
Nov 27, 2020·Drugs·Nicola SpecchioFederico Vigevano
Jan 8, 2021·Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft·V Behnke, T Langmann
Nov 30, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Robert J HuberClaire Russell
Oct 30, 2020·Journal of Neuroinflammation·Kristina BerveJanos Groh
Nov 4, 2020·International Journal of Molecular Sciences·Elena K Shematorova, George V Shpakovski
Jan 1, 2019·Expert Opinion on Orphan Drugs·Jonathan B RosenbergDolan Sondhi
Feb 11, 2021·Journal of Clinical Medicine·Athina-Maria AloizouEfthimios Dardiotis
Nov 5, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Hemanth R NelvagalJonathan D Cooper

❮ Previous
Next ❯

Methods Mentioned

BETA
electron microscopy
light microscopy
PCR
biopsies
flow cytometry
genotyping

Software Mentioned

Photoshop
ImageJ
Adobe
PASW Statistics
Power
CellQuest

Related Concepts

Related Feeds

Batten Disease

Batten Disease is a group of nervous system disorders known as neuronal ceroid lipofuscinosis. This feed focuses on neurobiological and neuropathological aspects of this disease.