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Review
. 2011 Jun;12(6):867-83.
doi: 10.2174/138920111795542633.

Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses

R Kohan  1 , I A Cismondi, A M Oller-Ramirez, N Guelbert, Tapia V Anzolini, G Alonso, S E Mole, Dodelson R de Kremer, Noher I de Halac
Affiliations
Review

Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses

R Kohan et al. Curr Pharm Biotechnol. 2011 Jun.

Abstract

The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 265 mutations and 38 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

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Figures

Fig. (1)
Fig. (1)
Strategy for NCL study: Diagnostic algorithm. Consensus reached at the 12th Congress on NCLs held in Hamburg-Germany 2009, coordinated by Dr. R. Williams. EM, Electron Microscopy.
Fig. (2)
Fig. (2)
Transport of a lysosomal enzyme in a normal cell, correction of storage in the cell of a patient with Mucopolysaccharidosis, and basis for ‘cross-correction’. The M6P recognition signal is added to the lysosomal enzyme precursor in the late-Golgi compartments, where enzyme modified by M6P binds to M6P receptors. The enzyme–receptor complex is packaged into a transport carrier vesicle and delivered to early endosomes in which low pH promotes the dissociation of the enzyme from the receptor. The enzyme is then delivered to the mature lysosome, and the M6P receptor is recycled to the Golgi apparatus. A small amount of the M6P–modified enzyme escapes capture by the M6P receptors and is released into the extra-cellular space. This enzyme can be recaptured by binding to a M6P receptor in a clathrin-coated pit on the cell surface. In a patient who has undergone hematopoietic stem-cell transplantation, enzyme released from a donor-derived stem cell can be taken up by a Mucopolysaccharidosis cell, which corrects aberrant glycosaminoglycan storage (from [Muenzer, J. & Fisher, A. (2004) Advances in the treatment of Mucopolysaccharidosis type I. New England Journal of Medicine 350(19):1932–4] Massachusetts Medical Society. All rights reserved, with permission of the editor).
Fig. (3)
Fig. (3)
A model of how blood-related stem cells may be related. The authors wish to acknowledge the suggestion of Ralf Huss, MD, PhD (from [Graham C. Parker. Blood Stem Cells and non-Hematological Clinical Practice: Pragmatics Before Therapeutics. Current Pharmaceutical Biotechnology, 2007, 8, 51-56], with permission of the editor).
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