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Gene-Based Treatment of Motor Neuron Diseases

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Gene-Based Treatment of Motor Neuron Diseases INVITED REVIEW ABSTRACT: Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neuro- degenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are de- signed to confer neuroprotection, using trophic factors, anti-apoptotic pro- teins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treat- ment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently at- tempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation. Muscle Nerve 33: 302–323, 2006 GENE-BASED TREATMENT OF MOTOR NEURON DISEASES THAIS FEDERICI, PhD,1 and NICHOLAS M. BOULIS, MD1,2 1 Department of Neuroscience, Cleveland Clinic Foundation, NB2-126A, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA 2 Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio, USA Accepted 5 August 2005 Motor neuron diseases (MND) are progressive neu- ginally effective. A detailed understanding of the rodegenerative disorders with different etiologies pathogenesis of MND remains elusive, and this gap and clinical variability, but a common final event: continues to impede the elaboration of specific treat- loss of upper and/or lower motor neurons. Amyo- ment strategies. Nonetheless, based on our limited trophic lateral sclerosis (ALS) and spinal muscular insight into the pathogenesis of the MNDs, a variety atrophy (SMA) are the most frequent forms of MND of approaches have emerged. Although these are not and therefore the most studied.100,144,184,185 Al- likely to be curative, they may provide life-prolong- though a variety of therapeutic trials in ALS and ing treatments. Gene-based treatment has several SMA are ongoing, available treatments remain mar- advantages over alternative paradigms that may de- liver these therapies for MND.5,29,167 Available for Category 1 CME credit through the AANEM at www. aanem.org. AMYOTROPHIC LATERAL SCLEROSIS Abbreviations: AAV, adeno-associated virus; ALS, amyotrophic lateral scle- rosis; BDNF, brain-derived neurotrophic factor; BHK, baby hamster kidney; ALS, also known as Lou Gehrig’s disease or adult CNS, central nervous system; CNTF, ciliary neurotrophic factor; CT-1, car- diotrophin-1; EAAT2, excitatory amino acid transporter 2; EIAV, equine infec- motor neuron disease, was first described by Charcot tious anemia virus; FALS, familial amyotrophic lateral sclerosis; GDNF, glial in 1869 and is the most common form of MND. ALS cell line–derived neurotrophic factor; GFAP, glial fibrillary acidic protein; GFP, green fluorescent protein; HIV-1, human immunodeficiency virus type 1; HSV, is characterized by a progressive degeneration of herpes simplex virus; IAPs, inhibitors of apoptosis proteins; IGF-1, insulin-like lower and upper motor neurons in the cerebral growth factor 1; MND, motor neuron diseases; NAIP, neuronal apoptosis inhibitory protein; NT-3, neurotrophin-3; p75NTR, p75 neurotrophin receptor; cortex, brainstem, and spinal cord. In turn, this neu- pmn, progressive motor neuropathy; PNA, peptide nucleic acid; RabG, rabies ronal loss causes weakness, spasticity, and muscular G protein; RNAi, RNA interference; SALS, sporadic amyotrophic lateral scle- rosis; siRNA, small interfering RNA; SMA, spinal muscular atrophy; SMN1 and atrophy that may evolve to paralysis. The disease SMN2, survival motor neuron gene; SOD1, copper–zinc superoxide dis- mutase; trk, receptor tyrosine kinases; VEGF, vascular endothelial growth culminates in death within 2–5 years of onset, gen- factor; VSV-G, vesicular stomatitis virus G glycoprotein; XIAP, X-linked inhib- erally due to respiratory failure. To date, ALS re- itors of apoptosis protein Key words: amyotrophic lateral sclerosis; gene therapy; retrograde axonal mains untreatable and all therapeutic trials are transport; spinal muscular atrophy; viral vectors merely palliative.47,100,184,185 N. M. Boulis; e-mail: [email protected] Correspondence to: ALS is a multifactorial disease, with etiological © 2005 Wiley Periodicals, Inc. Published online 14 October 2005 in Wiley InterScience (www.interscience. heterogeneity and a high variability of clinical pre- wiley.com). DOI 10.1002/mus.20439 sentation. The sporadic form (SALS) is widely pre- 302 Motor Neuron Diseases and Gene Therapy MUSCLE & NERVE March 2006 dominant, including approximately 90% of all cases, androgen receptor gene.66,90,100,170 As with ALS, clin- whereas the familial variant (FALS) affects less than ical trials have made no significant impact on SMA 10% of these patients and is usually autosomal-dom- survival. inant.61,184,185 Close to 20% of familial cases have been found to RESEARCH have mutations in the copper–zinc (Cu/Zn) super- oxide dismutase-1 (SOD1) gene on chromosome Research using animal models that reproduce the 21q.91,163 Over 100 different mutations of the SOD1 phenotype of MND has provided substantial insight 21,58 gene have already been described and several trans- into the human disease over the past decade. genic animal models for the SOD1 gene mutation There are many different mouse models for ALS, have been created.77,161 including those with spontaneous mutations, such as No satisfactory treatment is available for ALS at the motor neuron degenerative (mnd) mouse, the this time. Patient care focuses on symptomatic treat- wasted mouse, the wobbler mouse, and the progres- ment and physical therapy. Assisted ventilation and sive motor neuronopathy (pmn) mouse; and geneti- nutrition can transiently overcome the loss of upper cally engineered mice, such as the SOD1 transgenic airway and respiratory muscular control. A large mouse and the transgenic mouse that overexpresses number of therapeutic trials have been attempted. mutant neurofilaments. Although all these models Nonetheless, it was not until 1996 that the first drug are complementary and very helpful, the complex approved by the FDA for the treatment of patients etiology of ALS remains unclear and more studies with ALS reached the market. Riluzole is an anti- are required to provide therapies capable of prevent- glutamatergic substance that blocks the presynaptic ing or slowing the disease course.197 release of glutamate.103,104 The efficacy of riluzole is In the case of SMA, as SMN is a highly expressed questionable, however, with minimal therapeutic protein essential for survival, the development of benefits.177 animal models is extremely difficult. For example, the attempt to create a complete SMN knockout in 172 SPINAL MUSCULAR ATROPHY mice was hampered by its embryonic lethality. In fact, the age at onset of disease is a challenge among SMA is the generic name for a heterogeneous group all the different mice models of MND. More re- of diseases characterized by the degeneration of mo- cently, the creation of several mouse models, includ- tor neurons in the anterior horn of the spinal cord ing the novel SMN knockout mouse,66,144 has facili- and the brainstem (lower motor neurons), causing tated improved understanding of SMA and the progressive muscle weakness and atrophy. Like ALS, development of therapeutic strategies. SMA is invariably fatal. SMA remains one of the most Currently gene therapy is among the most prom- frequent genetic causes of death in childhood.43,144 ising treatments for ALS5,29,59,133 and SMA.13,55,110 The classification of SMA is controversial and This review focuses on the gene-based treatment of includes several forms, separated according to age of motor neuron diseases in general, surveying the po- onset, severity of symptoms, and evolution. Pediatric tential viral vector candidates, delivery strategies, SMA can be roughly divided into three forms: type 1, and main therapeutic approaches that have severe, infantile, also known as Werdnig–Hoffmann emerged. Finally, recent progress and potential fu- disease; type 2, the intermediate form; and type 3, ture strategies toward an effective motor neuron mild, juvenile, also called Kugelberg–Welander dis- gene therapy are also discussed, with emphasis on ease. Adult SMA includes distinct complex syn- ALS and SMA. dromes. One example is Kennedy’s syndrome, also known as progressive spinal and bulbar muscular PATHOGENESIS atrophy.43,46,90,100 The childhood forms, although phenotypically Several mechanisms have been postulated to explain different, are recessive autosomal disorders. The ma- motor neuron death in ALS. However, none of these jority are caused by homozygous deletion or muta- is completely satisfactory to elucidate the entire pro- tions in the telomeric copy of the survival motor cess.58,177,184 Among the proposed mechanisms, glu- neuron gene (SMN1) on chromosome 5q, which tamatergic oxidation and excitotoxicity have been codes the functional copy of the SMN protein. explored in the greatest depth. This mechanism pos- Kennedy’s disease, by contrast, is an X-linked reces- tulates that an excess of glutamate outside of the sive disorder and its molecular basis resides in the motor neuron, probably caused by
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