Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease)

TY - JOUR

T1 - Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease)

AU - Hawkins-Salsbury, Jacqueline A.

AU - Cooper, Jonathan D.

AU - Sands, Mark S.

PY - 2013/11

Y1 - 2013/11

N2 - The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases. Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the lifespan of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as juvenile neuronal ceroid lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

AB - The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases. Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the lifespan of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as juvenile neuronal ceroid lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

KW - Neuronal ceroid lipofuscinosis

KW - Batten disease

KW - Neurodegeneration

KW - Neuroinflammation

KW - Lysosomal storage disease

KW - Gene therapy

KW - PALMITOYL-PROTEIN THIOESTERASE

KW - CENTRAL-NERVOUS-SYSTEM

KW - BONE-MARROW-TRANSPLANTATION

KW - ENZYME REPLACEMENT THERAPY

KW - DIRECTED GENE-THERAPY

KW - MOUSE MODEL

KW - BATTEN-DISEASE

KW - MURINE MODEL

KW - LYSOSOMAL STORAGE

KW - STEM-CELLS

U2 - 10.1016/j.bbadis.2013.05.026

DO - 10.1016/j.bbadis.2013.05.026

M3 - Literature review

SN - 0925-4439

VL - 1832

SP - 1906

EP - 1909

JO - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

IS - 11

M1 - N/A

ER -