Gene therapy for neurodegenerative diseases based on lentiviral vectors

https://doi.org/10.1016/S0079-6123(09)17513-1Get rights and content

Abstract

Gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches. For neurodegenerative diseases, gene therapy is particularly attractive due to the restricted bioavailability of conventional therapeutic substances to the affected structures of the brain and progressive nature of these diseases. With the development of lentiviral vector systems, many issues have been addressed and new delivery routes to the nervous system have been identified. Lentiviral vectors can efficiently deliver genes to postmitotic neuronal cell types offering long-term expression, can be generated in high titers, and do not give immunological complications. Various animal studies have demonstrated the effectiveness of these vectors to deliver therapeutic genes into the nervous system, as well as to model human diseases. This chapter will describe the basic features of lentiviral vectors, the progress, and their applications as a therapeutic strategy to treat diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, Parkinson's disease, and Huntington's disease.

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)

  • A.P. Kells et al.

    AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease

    Molecular Therapy

    (2004)
  • J.H. Kordower et al.

    Lentiviral gene transfer to the nonhuman primate brain

    Experimental Neurology

    (1999)
  • S. Lefebvre et al.

    Identification and characterization of a spinal muscular atrophy-determining gene

    Cell

    (1995)
  • J.L. McBride et al.

    Structural and functional neuroprotection in a rat model of Huntington's disease by viral gene transfer of GDNF

    Experimental Neurology

    (2003)
  • G.Z. Mentis et al.

    Transduction of motor neurons and muscle fibers by intramuscular injection of HIV-1-based vectors pseudotyped with select rabies virus glycoproteins

    Journal of Neuroscience Methods

    (2006)
  • T.L. Munsat et al.

    International SMA consortium meeting. (26–28 June 1992, Bonn, Germany)

    Neuromuscular Disorders

    (1992)
  • D.W. Parsons et al.

    Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number

    American Journal of Human Genetics

    (1998)
  • L. Pellizzoni et al.

    A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing

    Cell

    (1998)
  • N. Popovic et al.

    Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes

    Experimental Neurology

    (2005)
  • R.C. Roberts et al.

    Intrastriatal injections of quinolinic acid or kainic acid: differential patterns of cell survival and the effects of data analysis on outcome

    Experimental Neurology

    (1993)
  • F. Saudou et al.

    Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions

    Cell

    (1998)
  • U. Ungerstedt

    6-Hydroxy-dopamine induced degeneration of central monoamine neurons

    European Journal of Pharmacology

    (1968)
  • Y.L. Wang et al.

    Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA

    Neuroscience Research

    (2005)
  • D.B. Williams et al.

    Motor neuron disease (amyotrophic lateral sclerosis)

    Mayo Clinic Proceedings

    (1991)
  • L.F. Wong et al.

    Transduction patterns of pseudotyped lentiviral vectors in the nervous system

    Molecular Therapy

    (2004)
  • A. Yamamoto et al.

    Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease

    Cell

    (2000)
  • M. Azzouz et al.

    Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy

    The Journal of Clinical Investigation

    (2004)
  • M. Azzouz et al.

    Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease

    The Journal of Neuroscience

    (2002)
  • M. Azzouz et al.

    VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model

    Nature

    (2004)
  • M. Azzouz et al.

    Neuroprotection in a rat Parkinson model by GDNF gene therapy using EIAV vector

    Neuroreport

    (2004)
  • A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III)

    Neurology

    (1999)
  • A.C. Belin et al.

    Parkinson's disease: a genetic perspective

    The FEBS Journal

    (2008)
  • G.D. Borasio et al.

    A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group

    Neurology

    (1998)
  • J.M. Brotchie et al.

    Levodopa-induced dyskinesia in Parkinson's disease

    Journal of Neural Transmission

    (2005)
  • S.E. Browne et al.

    The energetics of Huntington's disease

    Neurochemical Research

    (2004)
  • L.M. Brzustowicz et al.

    Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3

    Nature

    (1990)
  • L.P. de Almeida et al.

    Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length

    The Journal of Neuroscience

    (2002)
  • M. DiFiglia et al.

    Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain

    Science

    (1997)
  • E. Dowd et al.

    Lentivector-mediated delivery of GDNF protects complex motor functions relevant to human Parkinsonism in a rat lesion model

    The European Journal of Neuroscience

    (2005)
  • A.W. Dunah et al.

    Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease

    Science

    (2002)
  • S.B. Dunnett et al.

    Prospects for new restorative and neuroprotective treatments in Parkinson's disease

    Nature

    (1999)
  • E. Ekestern

    Neurotrophic factors and amyotrophic lateral sclerosis

    Neuro-degenerative Diseases

    (2004)
  • M. Eriksdotter Jonhagen et al.

    Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease

    Dementia and Geriatric Cognitive Disorders

    (1998)
  • M.B. Feany et al.

    A Drosophila model of Parkinson's disease

    Nature

    (2000)
  • L.S. Forno et al.

    Similarities and differences between MPTP-induced parkinsonism and Parkinson's disease. Neuropathologic considerations

    Advances in Neurology

    (1993)
  • Gene Therapy Clinical Trials Worldwide. (2008). Journal of Gene Medicine, Wiley, available at:...
  • B. Georgievska et al.

    Neuroprotection in the rat Parkinson model by intrastriatal GDNF gene transfer using a lentiviral vector

    Neuroreport

    (2002)
  • W.R. Gibb et al.

    The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease

    Journal of Neurology, Neurosurgery, and Psychiatry

    (1988)
  • J.M. Gil et al.

    Mechanisms of neurodegeneration in Huntington's disease

    The European Journal of Neuroscience

    (2008)
  • M.E. Gurney et al.

    Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis

    Annals of Neurology

    (1996)
  • Cited by (0)

    View full text