New therapeutic targets for neuronal ceroid lipofuscinosis (Batten disease)

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

The Neuronal Ceroid Lipofuscinoses (NCLs) are a group of 13 inherited neurodegenerative lysosomal storage disorders (LSDs) that mainly affect children and young adults. While individually rare, together they form the most common cause of childhood dementia. Age of onset and order of symptoms can vary drastically between the different forms of NCL, but common features include the accumulation of autofluorescent storage material (AFSM), glial activation, neuronal loss, visual loss, seizures, motor and cognitive regression and an early death. Only one treatment for NCL has been clinically approved to treat CLN2 disease. However, as the treatment is not curative, all forms of NCL remain fatal. The development of treatments has been especially arduous for the transmembrane protein deficient forms of NCL, as they cannot rely on the principle of cross correction and require potential treatments, such as gene therapy, to be targeted to all sites of pathology. Recently the spinal cord has emerged as an essential target for treatment in CLN1 disease and targeting both the spinal cord and brain has achieved therapeutic successes greater than the sum of either treatment alone. Considering the heterogeneity of the NCLs, as well as their commonalities, exploring the presence of pathology outside the brain in other forms of NCL, particularly the transmembrane protein deficient ones, is essential to develop appropriately targeted treatments. Here, we characterised the onset and progression of spinal cord pathology in mouse models of two transmembrane protein deficient forms of NCL, Cln3 and Cln7 diseases, as well as the involvement of the sensory afferent system and PNS in disease phenotype at end stage disease. Spinal cord pathology was detected in both Cln3Δex7/8 and Cln7Δex2 mice but presented with different severity and times of onset. Pathological changes included neuronal loss, atrophy, glial activation and accumulation of AFSM, as well as sensory afferent sprouting in the Cln7Δex2 spinal cord. While the peripheral nervous system (PNS) showed no signs of pathology, apart from the accumulation of AFSM, changes in the perineuronal net were reported for the first time in any form of NCL in the brain and spinal cord of end stage Cln7Δex2 mice. These data, for the first time, provide evidence for pathology in the spinal cord of Cln3 and Cln7 diseases, suggesting that targeting treatment to the spinal cord might be beneficial in these forms of NCL. In addition, the involvement of the sensory afferent system and perineuronal net in Cln7Δex2 mice highlight the need to look for pathology further afield as successful treatment of the CNS becomes a possibility for the NCLs. Lastly, the differences in the pathological phenotypes between Cln3Δex7/8  and Cln7Δex2 mice emphasise the need to continue to assess each NCL individually, rather than as a homogenous group of diseases.
Date of Award1 May 2020
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJonathan Cooper (Supervisor), Elizabeth Bradbury (Supervisor) & Sandrine Thuret (Supervisor)

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