Gene therapy for neurodegenerative diseases based on lentiviral vectors
Section snippets
Principle of gene therapy and gene transfer vehicles
Gene therapy is not just limited to the replacement of a defective gene with a functional one, but it describes any nucleic acid transfer to treat or prevent disease and provides many advantages over conventional therapeutic strategies, such as the selective treatment of affected cells and long-term treatment after a single application. Different gene therapy systems have been generated, including viral vectors, nonviral synthetic vectors such as naked DNA and cationic liposomes (Li and Huang,
Clinical symptoms and current treatment
Amyotrophic lateral sclerosis or motor neuron disease (ALS or MND, also known as Lou Gehrig's disease) is a progressive neurodegenerative disorder that is characterized by the loss of upper and lower motor neurons of the spinal cord, brain stem, and motor cortex (Mulder, 1982). The progressive manifestations of upper and lower motor neuron dysfunction include muscle weakness and wasting usually accompanied by pathologically brisk reflexes, eventually involving the limb and bulbar muscles. It is
Clinical manifestations and genetics of spinal muscular atrophy
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disease characterized by the degeneration of the anterior horn motor neurons of the spinal cord and is associated with symmetrical limb and trunk paralysis with muscle atrophy. SMA disease severity is heterogeneous, and its clinical manifestations are divided into four types (Table 3) depending on age of onset and clinical course (Munsat and Davies, 1992; Russman, 2007).
All four types were found to be caused by
Clinical symptoms
Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder (after Alzheimer's disease), and it is primarily, but not exclusively, characterized by the selective loss of the dopaminergic neurons in the substantia nigra pars compacta (SNpc) and thus the depletion of the neurotransmitter dopamine (DA) in the striatum. The mean age at onset is 50–60 years, and the clinical symptoms include rigidity, resting tremor, bradykinesia, and postural instability (Lang and
Huntington's disease: a polyglutamine disorder
Huntington's disease (HD) belongs to a heterogeneous class of at least nine genetically distinct disorders, termed polyglutamine disorders, which are caused by the expansion of trinucleotide repeats coding for polyglutamine tracts in respective proteins (Nakamura et al., 2001; Zoghbi and Orr, 2000). HD is an inherited progressive neurodegenerative disorder with the onset of disease being between the ages 35 and 50 years, and the clinical symptoms include involuntary (choreic) movements,
Clinical prospects and challenges of lentiviral vectors
Lentiviral vector-mediated gene therapy offers many advantages compared to other viral systems and, as a therapeutic approach, is very attractive particularly for neurodegenerative disorders since it can be delivered to the affected area, and one treatment offers long-term expression. Currently, only one clinical trial is ongoing with lentiviral vectors for PD patients, but with the growing knowledge of the pathogenic mechanisms of all neurodegenerative diseases, new candidates for gene therapy
Abbreviations
- 6-OHDA
6-hydroxydopamine
- AAV
adeno-associated virus
- ALS
amyotrophic lateral sclerosis
- BIV
bovine immunodeficiency virus
- CAG
cytosine–adenine–guanine
- CNS
central nervous system
- CNTF
ciliary neurotrophic factor
- DA
dopamine
- EIAV
equine infectious anemia virus
- FIV
feline immunodeficiency virus
- GABA
gamma aminobutyric acid
- GDNF
glial-derived neurotrophic factor
- HD
Huntington's disease
- HIV
human immunodeficiency virus
- LRRK2
leucine-rich repeat kinase 2
- MND
motor neuron disease
- MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine
- PD
References (106)
- et al.
Alpha-synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: lessons from viral transduction of knockout mice
Neuroscience Letters
(2008) - et al.
Lentiviral vectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF
Experimental Neurology
(2000) - et al.
Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration
Cell
(2006) - et al.
Parkinson's disease: mechanisms and models
Neuron
(2003) - et al.
Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington's disease
Neurobiology of Disease
(2001) - et al.
Quantitative analyses of SMN1 and SMN2 based on real-time LightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
American Journal of Human Genetics
(2002) - et al.
Efficient in vivo protection of nigral dopaminergic neurons by lentiviral gene transfer of a modified Neurturin construct
Experimental Neurology
(2005) - et al.
AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease
Molecular Therapy
(2008) - et al.
Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease
Molecular Therapy
(2007) - et al.
Local GDNF expression mediated by lentiviral vector protects facial nerve motoneurons but not spinal motoneurons in SOD1(G93A) transgenic mice
Neurobiology of Disease
(2004)