Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by progressive muscle wasting, inanition, respiratory failure, and death within approximately 2 to 5 years of onset. ALS is among the most common neuromuscular conditions, with an overall prevalence in the world of ~ 5 to 7 cases/100,000 population. Epidemiologic studies have identified some potential risk factors for developing ALS, including a high-fat, low-fiber diet; cigarette smoking; slimness and athleticism; and living in urban areas. Between 5% and 10% of ALS is genetic, with up to 11 genetic loci identified. Although understanding of the pathophysiology of this disease has advanced over the past 60 years, scant progress has been made regarding effective treatment. The authors review the current understanding of the pathogenic mechanisms of ALS and approaches to treating the disease.
Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by progressive muscle wasting, inanition, respiratory failure, and death within approximately 2 to 5 years of onset. ALS is among the most common neuromuscular conditions, with an overall prevalence in the world of ∼5 to 7 cases/100,000 population . The incidence of ALS may be increasing, possibly because of better recognition of the diagnosis and increased life expectancy . The disease most commonly afflicts middle-aged individuals between 40 and 60 years of age . Men are more commonly affected than women, with a ratio of ∼1.5:1 . Epidemiologic studies have identified some potential risk factors for developing ALS, including high dietary glutamate, high dietary fat, and low fiber intake ; cigarette smoking ; slimness and athleticism ; and living in urban areas. Between 5% and 10% of ALS is genetic, with up to 11 genetic loci identified . Although understanding of the pathophysiology of this disease has advanced over the past 60 years, scant progress has been made regarding effective treatment. The authors review the current understanding of the pathogenic mechanisms of ALS and approaches to treating the disease.
Mechanisms of disease
ALS is a progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons present in the motor cortex, brain stem, and spinal cord. The fundamental pathophysiology of ALS is still not understood, but extensive research in this field has identified several potential pathogenic mechanisms. A better understanding of the mechanisms that result in motor neuron death will facilitate the development of methods to treat this devastating illness more effectively.
Genetics
ALS can be divided into two clinically indistinguishable forms: familial (FALS) and sporadic (SALS). FALS is defined by a family history of ALS, and approximately 10% of cases are familial . Of the familial cases, 10% to 20% are associated with mutations in the super oxide dismutase 1 (SOD1) gene on chromosome 21q12.1, inherited as an autosomal dominant trait . This gene codes for Cu, Zn-superoxide dismutase, which catalyzes the conversion of superoxide into hydrogen peroxide and oxygen. Mutations result in a toxic gain of function, which is still not completely understood.
Other genetic factors, which may prove to be susceptibility genes, have been described in SALS and FALS. Haplotypes in the promoter of vascular endothelial growth factor , the presence of an apolipoprotein E4 allele , and single nucleotide polymorphisms in the paraoxonase genes are associated with an increased risk for developing SALS. Mutations in cytoskeletal proteins have been described in patients who have ALS, including neurofilament heavy chain subunit , peripherin , and dynactin . Recently, whole-genome association analysis has been used to search for genes involved in ALS. Three positive studies have identified three leading gene candidates: FLJ10986 , inositol 1,4,5-triphosphate receptor 2 , and dipeptidyl-peptidase 6 . The contribution of whole-genome association studies to our understanding of ALS is not yet clear.
Excitotoxicity
Excitotoxicity results from the overstimulation of neuronal glutamate receptors, which leads to an excessive influx of calcium into the neuron and can ultimately lead to cell death. Motor neurons are particularly susceptible to excitotoxicity because of a high number of Ca 2+ -permeable alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors and a low Ca 2+ -buffering capacity . MR spectroscopy indicated that glutamate levels were increased in the plasma of patients who had ALS and in the medulla of patients who had ALS . Patients who have ALS have reduced levels of high-affinity glutamate transport in the spinal cord and somatosensory cortex caused by a selective loss of the glial excitatory amino acid glutamate transporter-2 . Cerebrospinal fluid from patients who have ALS is toxic to neuronal cell cultures by activation of AMPA receptors and increased intracellular Ca 2+ .
Apoptosis
Apoptosis, or programmed cell death, has been implicated in ALS , with decreased levels of Bcl-2 mRNA (an antiapoptotic gene) and increased levels of bax mRNA (a proapoptotic gene) in the spinal cords of patients who have the disease . Caspases are the major effectors of the apoptosis cascade, and activation of caspases is seen in spinal cord tissue from patients who have ALS and in ALS transgenic mice . Localization of mutant SOD1 to the mitochondria induces cell death in a caspase-dependent manner in neuronal cells . A caspase inhibitor, zVAD-fmk, delayed disease onset and mortality in transgenic ALS mice .
Oxidative stress and mitochondrial dysfunction
Oxidative stress is the abnormal balance between the production of reactive oxygen species such as superoxide, hydrogen peroxide, and hydroxyl radical, and the removal of reactive oxygen species by the antioxidant system. Studies of postmortem tissue from patients who had ALS have shown accumulation of oxidative damage in proteins, lipids, and DNA .
In ALS, histologic abnormalities have been observed in the mitochondria in proximal axons , spinal cords , and dorsal root ganglia of patients. Mitochondria are important in maintaining low cytosolic levels of calcium (Ca 2+ ) by contributing to handling rapid cytosolic Ca 2+ transients. Mitochondrial Ca 2+ accumulation seems to play a key role in glutamate excitotoxicity. Thus, mitochondrial dysfunction and Ca 2+ -mediated excitotoxicity likely contribute to neuronal degeneration in FALS. Also, the Ca 2+ capacity of mitochondria is impaired in ALS transgenic mice before the onset of motor symptoms . Mutant SOD1 has been found to form aggregates in the mitochondria that can alter the reduction oxidation balance , damage mitochondrial proteins , and lead to release of cytochrome C . Oxidation of wild-type SOD1 results in acquisition of toxic properties seen in the FALS mutant SOD1 , raising the possibility that involvement of SOD1 also occurs in SALS.
Neuroinflammation
Microglia are the resident macrophages of the central nervous system, normally functioning to remove cellular debris, facilitate repair, and enhance neuronal survival by way of production of trophic and anti-inflammatory factors. However, overactivation can be detrimental because of production of cytotoxic factors such as superoxide, nitric oxide, and tumor necrosis factor, and microglia have been implicated in several neurodegenerative diseases . Selective expression of FALS mutant SOD1 in neurons is not sufficient for development of motor neuron disease in mice . Microglia show activation in ALS transgenic mice before the development of motor neuron disease . In chimeric mice, motor neurons expressing FALS mutant SOD1 showed prolonged survival when surrounded by wild-type glial cells , and transplantation of wild-type microglia into an ALS mouse resulted in slower progression but did not affect onset . Microglia produce NADPH oxidase, which catalyzes the production of reactive oxygen species during inflammation, and is up-regulated in the spinal cords of patients who have ALS and ALS transgenic mice. Deletion of the catalytic subunit lengthens survival . A recent study showed that SOD1 binds to the G-protein Rac1 and modulates its activity as a redox sensor; this process is defective in SOD1 mutants, leading to enhanced activation of NADPH oxidase . Also, treatment of ALS transgenic mice with an inhibitor of NADPH oxidase, apocyanin, slows disease progression and increases lifespan, raising the possibility of a therapeutic target in humans .
Protein aggregation
Several neurodegenerative diseases are characterized by the formation of intracellular inclusions, and several inclusions have been described in neuropathologic studies of ALS. These inclusions may contain cystatin C and ubiquitin , hyaline, Lewy-body–like hyaline, astrocytic hyaline with immunoreactivity to SOD1 and ubiquitin , and phosphorylated neurofilament protein . Mutations in SOD1 appear to cause protein aggregation in vitro and in vivo . The formation of SOD1 aggregates is associated with neurodegeneration in mouse models of ALS, and these aggregates are present in the mitochondria . The increased aggregation of SOD1 in ALS may disrupt the cellular pathways involved in protein chaperoning and degradation.
Therapeutic trials
The most commonly used model of ALS is the G93A mouse (SOD1G93A). This mouse is genetically engineered to express a mutant form of the human SOD1 gene, and harbors the glycine to alanine mutation at amino acid 93 (hence G93A). Since the development of the SOD1 mouse model of ALS , numerous therapeutic trials in SOD1 mice have taken place. The choice of therapeutic agents in many clinical trials of human ALS has been dictated, at least in part, by the success of these agents in the SOD1 mouse . Efficacy in human clinical trials has been limited, however, raising doubts about the value of the model in screening therapies for ALS .
Riluzole
Despite clinical use for more than 14 years, riluzole, a 2-amino-6-(trifluoromethoxy) benzothiozole, remains the only Food and Drug Administration–approved medication proved to slow the progression of ALS. Pharmacologic mechanisms of riluzole include interference with N-methyl-D-aspartate (NMDA)-receptor mediated responses, stabilization of the inactivated state of voltage-dependent sodium channels, inhibition of glutamate release from synaptic terminals, and activation of extracellular glutamate uptake. Riluzole has demonstrated neuroprotective effect in motor neuron cultures and SOD1G93A transgenic mice . A recent Cochrane Database Review concluded riluzole, 100 mg (total dose per day), prolongs median survival by about 2 to 3 months, based on analysis of four randomized controlled trials . Recent studies using large registries suggest a greater benefit, ranging from 4 to 20 months . Although American Academy of Neurology practice guidelines recommend the use of riluzole for nonventilated patients who have ALS, analysis of the ALS CARE Database found that 41% of the cohort was not prescribed this medication, largely because of the expense . The drug is generally well tolerated, with asthenia, nausea, and an increase in serum alanine aminotransferase the most common side effects . Liver function should be monitored during therapy.
Growth factors
Growth factors represent a large, heterogeneous group of endogenous polypeptides with varying physiologic activity, including cell signaling, cellular growth and differentiation, angiogenesis, regulation of inflammation, and antiapoptotic effect. Growth factor clinical trials to date have been disappointing. Treatment with subcutaneous recombinant human insulin-like growth factor-1 (rhIGF-1 or myotrophin) for 9 months slowed deterioration on the Appel ALS rating scale in a multicenter, North American trial but not in a similarly designed European study that may have been statistically underpowered . A 2007 Cochrane Database Review concluded that available data were insufficient to render definitive assessment of rhIGF-1 as a clinical therapy for treatment of ALS . A third phase III study is currently complete and results are pending. Neurotrophins, including brain-derived neurotrophic factor, ciliary neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF), and oral xaliproden, which has neurotrophic-like activity, have failed to demonstrate benefit in human clinical trials . Vascular endothelial growth factor, erythropoietin, and hepatocyte growth factor slow motor neuron deterioration in vitro and prolong survival in transgenic ALS rodent models but, to date, no human trial data have been reported .
Antiexcitotoxic/reducing glutamate
Ceftriaxone
Ceftriaxone increased brain expression of astroglial glutamate transporter 1 and its biochemical and functional activity, and delayed the loss of neurons and muscle strength, associated with increased mouse survival. Its central nervous system penetration and long half-life are well known, obviating the need for extensive safety trials . Stage I of the clinical trial has now been completed.
Memantine
Memantine is a noncompetitive NMDA receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro. Treatment of SOD1G93A mice significantly delayed disease progression and increased life span . Safety studies are completed, and efficacy studies are enrolling patients (Clinicaltrials.gov NCT00409721 & NCT00353665).
N-acetylated alpha-linked acidic dipeptidase
Glutamate carboxypeptidase II (GCP II) N-acetylated alpha-linked acidic dipeptidase (NAALADase) inhibition decreases extracellular excitotoxic glutamate and increases extracellular N-acetylaspartylglutamate, both of which lead to increased neuroprotection . Selective GCP II inhibitors demonstrated efficacy in models of stroke, ALS , and neuropathic pain. GCP II inhibition may have benefits over existing glutamate-based neuroprotection strategies, being selective for excitotoxic-induced glutamate release, with potentially fewer side effects. Phase I studies showed GCP II inhibition to be safe and well tolerated by healthy volunteers and patients who had diabetes .
ONO-2506
ONO-2506 is an enantiomeric homolog of valproate that restores disturbed astrocyte functions . Subgroup analysis of a phase II trial suggested slowed respiratory deterioration in patients, with shorter duration disease (Public Relations, Ono Pharmaceutical Co., Ltd., August 10, 2005). A phase III trial of valproate has completed enrollment (Clinicaltrials.gov NCT00403104).
Talampanel (8-methyl-7H-1,3-dioxolo(2,3)benzodiazepine)
Talampanel (8-methyl-7H-1,3-dioxolo(2,3)benzodiazepine) is a noncompetitive modulator of AMPA glutamate receptors that crosses the blood–brain barrier and has prolonged SOD1G93A mouse survival. ALS functional rating scale (ALSFRS) and Tufts Quantitative Neuromuscular Examination (TQNE) scores declined at a slower rate in a 9-month phase II study of talampanel in 60 patients who had ALS .
Tamoxifen
Tamoxifen inhibits protein kinase C, and may reduce inflammation in the spinal cords of patients who have ALS . Tamoxifen extended survival in a virally induced ALS mouse model . In a phase II study of 60 patients who had ALS, tamoxifen prolonged survival .
Antiapoptosis
Minocycline
A tetracycline antibiotic, minocycline inhibits caspase activity by preventing its up-regulation, thereby decreasing motor neuron death. It also reduces glutamate-induced activation of microglia . Minocycline prolonged survival in mouse models of Huntington’s disease and FALS . In a controlled trial of minocycline (400 mg/day, n = 412), ALS functional rating scale-revised (ALSFRS-R) declined faster over 9 months in the treatment group. Strength and pulmonary function tended to decline faster, and increased mortality tended to increase .
TCH346
TCH346 (dibenz [b,f]oxepin-10-ylmethyl-prop-2-ynyl-amine, hydrogen maleate salt) prevents the apoptotic increases and the nuclear accumulation of the glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase. TCH346 (CGP 3466B) slowed disease progression in a murine model . In a controlled study of 554 subjects, TCH346 was evaluated at four different doses, with no significant differences in any outcome measures when compared with placebo .
Antioxidants
Arimoclomol
Overexpression of heat shock protein conferred protection from ischemic injury in mammalian brain . Arimoclomol, a coinducer of heat shock proteins, delayed progression of ALS in a mouse model . A dose-ranging phase II study has been completed and a phase III study is planned.
Coenzyme Q10 (CoQ10 or ubiquinone)
Mitochondrial dysfunction in ALS may be aided by coenzyme Q10 (CoQ10 or ubiquinone) . In SOD1G93A transgenic mice, low-dose CoQ10 prolonged median survival by 4.4% . Doses up to 3000 mg per day are safe and well tolerated in patients who have ALS . However, a phase III trial involving 185 people with ALS did not show any benefit over placebo .
Edaravone
The efficacy and safety of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one [MCI-186]), a free radical scavenger previously approved for treatment of acute cerebral infarction, was evaluated in patients who had ALS. Cerebrospinal fluid 3NT, a marker for oxidative stress, was reduced in a phase II trial. Decline in the ALSFRS-R score was significantly less than that in the 6 months before edaravone administration .
Melatonin
Melatonin is an amphiphilic molecule with antioxidative effects not conveyed by classic antioxidants. In SOD1G93A transgenic mice, high-dose oral melatonin extended survival. Rectal melatonin, 300 mg/day, was tolerated in a clinical safety study of 31 patients who had SALS .
Vitamin E
A study of vitamin E versus placebo in patients on riluzole yielded no difference in survival, although it showed a tendency to remain longer in the milder states of ALS with vitamin E . Five grams per day of vitamin E was well tolerated in a phase III trial. However, no significant difference in survival was noted between treatment groups .
Immunomodulatory/anti-inflammatory
Celecoxib
The anti-inflammatory celecoxib, a selective cyclooxygenase-2 inhibitor that demonstrated neuroprotective effects and prolonged longevity in SOD1G93A mice, failed to show benefit on strength measures or survival at 800 mg/day dosing in a large, randomized, placebo-controlled trial .
Creatine
Creatine has neuroprotective effects through blockade of the mitochondrial membrane pore and as an antioxidant , but failed to show benefit in two large, randomized, controlled trials .
Copaxone
Copolymer-1 (copaxone) induces a neuroprotective T cell-mediated response. ALS mice treated with copolymer-1 experienced delayed disease onset, improved motor function, and extended survival . Phase II trials of daily or biweekly injections demonstrated safety in the ALS population .
Thalidomide
Thalidomide reduced tumor necrosis factor–alpha, attenuated weight loss, and increased survival in SOD1 G93A mice . An open-label phase II trial of thalidomide is completed but the results have not been released.
Neurodegeneration
Lithium
Lithium prevents neurodegeneration by promoting autophagy through inhibition of inositol-monophosphatase; it also rescues spinal cord mitochondria and facilitates the clearance of alpha-synuclein, ubiquitin, and SOD1. It delayed disease onset and progression in G93A transgenic mice and increased survival and slowed progression in humans over 15 months, compared with controls .
Innovative approaches
Extensive ineffective clinical trials in ALS involving various subcutaneously and orally administered medications have been disappointing, which has led to novel approaches to drug delivery or nonpharmacologic forms of treatment.
Intrathecal delivery
Short half-life compounds, particularly neurotrophic factors, and larger molecules with poor penetration across the blood–brain barrier, may not achieve therapeutic concentrations in the brain and spinal cord. For this reason, intrathecal delivery of medications has been attempted in ALS. Intrathecal brain-derived neurotrophic factor in a phase I/II dose escalation study was found to be well tolerated, with spinal fluid levels directly related to dose administration . A small, double-blinded study of rhIGF-1 delivered intrathecally slowed motor deterioration on measures of total and limb Norris scales .
Gene therapy
Mechanisms for delivering gene transcripts directly to motor neuron cellular DNA by way of motor axonal retrograde transport include genetically engineered adeno-associated virus (AAV), which may be administered by intramuscular, intraperitoneal, and intravenous injection. The Bcl-xL gene, with antiexcitotoxic properties, incorporated with AAV-2 viral vector, was neuroprotective in a glutamate toxicity model in vitro , whereas intramuscularly injected GDNF- and insulin-like growth factor-AAV increased longevity in motor neuron cultures and G93A mice . AAV-2, with a coding gene for a small interference RNA to SOD1 and injected intramuscularly into G93A mice, decreased mutant SOD1 load and delayed loss of grip strength . Retrograde transport of intramuscularly injected conjugated recombinant human GDNF linked to neuronal binding fragment of tetanus toxin (tetanus toxin fragment C) produced intense immunostaining in spinal cord motor neurons, but without significant motor neuron preservation, as compared with GDNF in a neonatal rat axonotomy model . A phase I/II clinical trial involving implantation of encapsulated baby hamster kidney cells engineered to release human ciliary neurotrophic factor reported detectable cerebrospinal fluid levels of the neurotrophin in 9 of 12 study subjects, with 2 of these individuals having detectable levels up to 20 weeks postimplantation . No significant side effects were reported.
Stem cell transplant
Feasibility and safety studies of intraspinal cord implantation of autologous mesenchymal stem cells showed no convincing clinical benefits .
Cannabinoids (marijuana)
Several studies published show a significant benefit from cannabinoids, including delta-9-tetrahydrocannibinol (THC) in the SOD1 mouse model of ALS . Administration of delta-9-THC before and after the onset of ALS symptoms slowed disease progression and prolonged survival in animals, compared with untreated controls . Other trials in animal models of ALS have also shown that naturally occurring and synthetic cannabinoids slow down the progression of ALS . Another recent study showed that blocking the CB1 cannabinoid receptor extended the life span of mice that had ALS , which suggests that some abnormality within our internal cannabinoid system may be part of the underlying disease mechanisms in ALS. The cannabinoids are all 21 carbon terpenes, a chemical structure that is the same as tamoxifen. Similar to tamoxifen, cannabinoids inhibit protein kinase C, and could reduce inflammation in the spinal cord of patients who have ALS, although this remains to be studied.
Therapeutic exercise
Two studies have evaluated exercise, with some favorable response. In one, the decline of ALSFRS slowed , and the other showed improved quality of life with a trial of resistance exercise training ( Table 1 ) .
| Medication | Mechanism of action | Number of treated | Number of placebo | Outcome | References |
|---|---|---|---|---|---|
| Riluzole | Reduces glutamate | 907 | 503 | Prolonged survival 2–3 mo | (4 trials) |
| Talampanel | — | 60 a | — | Slowed decline in ALSFRS and TQNE | |
| Tamoxifen | — | 60 a | — | Prolonged survival | |
| BDNF | Growth factor | 748 | 387 | No improved survival; slowed rate of respiratory failure | |
| rhCNTF | — | 141 | 429 | No benefit | |
| rhCNTF | — | 485 | 245 | No benefit | |
| rhIGFI | — | 99 | 42 | Slowed deterioration | |
| rhIGF | — | 124 | 59 | No significant difference | |
| GDNF | — | NA | — | No benefit | |
| Xaliproden | — | 1385 | 690 | No benefit | |
| Minocycline | Inhibitor of neuronal apoptosis | 206 | 206 | Worsened decline on ALSFRS and increased mortality | |
| TCH346 | — | 442 | 111 | No benefit | |
| Edaravone | Antioxidant | 20 b | — | Slowed decline on ALSFRS-R | |
| Coenzyme Q10 | — | 185 a | — | No benefit | |
| Vitamin E | — | 83 | 77 | No change in survival | |
| Celecoxib | Anti-inflammatory | 201 | 99 | No benefit | |
| Creatine | — | 138 | 141 | No benefit | (2 trials) |
| Copaxone | — | 20 | 10 | No conclusions about benefit | |
| Lithium | Prevents neurodegeneration | 16 | 28 | Increased survival, slowed progression | |
a Only total patient numbers available.
Therapeutic trials
The most commonly used model of ALS is the G93A mouse (SOD1G93A). This mouse is genetically engineered to express a mutant form of the human SOD1 gene, and harbors the glycine to alanine mutation at amino acid 93 (hence G93A). Since the development of the SOD1 mouse model of ALS , numerous therapeutic trials in SOD1 mice have taken place. The choice of therapeutic agents in many clinical trials of human ALS has been dictated, at least in part, by the success of these agents in the SOD1 mouse . Efficacy in human clinical trials has been limited, however, raising doubts about the value of the model in screening therapies for ALS .
Riluzole
Despite clinical use for more than 14 years, riluzole, a 2-amino-6-(trifluoromethoxy) benzothiozole, remains the only Food and Drug Administration–approved medication proved to slow the progression of ALS. Pharmacologic mechanisms of riluzole include interference with N-methyl-D-aspartate (NMDA)-receptor mediated responses, stabilization of the inactivated state of voltage-dependent sodium channels, inhibition of glutamate release from synaptic terminals, and activation of extracellular glutamate uptake. Riluzole has demonstrated neuroprotective effect in motor neuron cultures and SOD1G93A transgenic mice . A recent Cochrane Database Review concluded riluzole, 100 mg (total dose per day), prolongs median survival by about 2 to 3 months, based on analysis of four randomized controlled trials . Recent studies using large registries suggest a greater benefit, ranging from 4 to 20 months . Although American Academy of Neurology practice guidelines recommend the use of riluzole for nonventilated patients who have ALS, analysis of the ALS CARE Database found that 41% of the cohort was not prescribed this medication, largely because of the expense . The drug is generally well tolerated, with asthenia, nausea, and an increase in serum alanine aminotransferase the most common side effects . Liver function should be monitored during therapy.
Growth factors
Growth factors represent a large, heterogeneous group of endogenous polypeptides with varying physiologic activity, including cell signaling, cellular growth and differentiation, angiogenesis, regulation of inflammation, and antiapoptotic effect. Growth factor clinical trials to date have been disappointing. Treatment with subcutaneous recombinant human insulin-like growth factor-1 (rhIGF-1 or myotrophin) for 9 months slowed deterioration on the Appel ALS rating scale in a multicenter, North American trial but not in a similarly designed European study that may have been statistically underpowered . A 2007 Cochrane Database Review concluded that available data were insufficient to render definitive assessment of rhIGF-1 as a clinical therapy for treatment of ALS . A third phase III study is currently complete and results are pending. Neurotrophins, including brain-derived neurotrophic factor, ciliary neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF), and oral xaliproden, which has neurotrophic-like activity, have failed to demonstrate benefit in human clinical trials . Vascular endothelial growth factor, erythropoietin, and hepatocyte growth factor slow motor neuron deterioration in vitro and prolong survival in transgenic ALS rodent models but, to date, no human trial data have been reported .
Antiexcitotoxic/reducing glutamate
Ceftriaxone
Ceftriaxone increased brain expression of astroglial glutamate transporter 1 and its biochemical and functional activity, and delayed the loss of neurons and muscle strength, associated with increased mouse survival. Its central nervous system penetration and long half-life are well known, obviating the need for extensive safety trials . Stage I of the clinical trial has now been completed.
Memantine
Memantine is a noncompetitive NMDA receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro. Treatment of SOD1G93A mice significantly delayed disease progression and increased life span . Safety studies are completed, and efficacy studies are enrolling patients (Clinicaltrials.gov NCT00409721 & NCT00353665).
N-acetylated alpha-linked acidic dipeptidase
Glutamate carboxypeptidase II (GCP II) N-acetylated alpha-linked acidic dipeptidase (NAALADase) inhibition decreases extracellular excitotoxic glutamate and increases extracellular N-acetylaspartylglutamate, both of which lead to increased neuroprotection . Selective GCP II inhibitors demonstrated efficacy in models of stroke, ALS , and neuropathic pain. GCP II inhibition may have benefits over existing glutamate-based neuroprotection strategies, being selective for excitotoxic-induced glutamate release, with potentially fewer side effects. Phase I studies showed GCP II inhibition to be safe and well tolerated by healthy volunteers and patients who had diabetes .
ONO-2506
ONO-2506 is an enantiomeric homolog of valproate that restores disturbed astrocyte functions . Subgroup analysis of a phase II trial suggested slowed respiratory deterioration in patients, with shorter duration disease (Public Relations, Ono Pharmaceutical Co., Ltd., August 10, 2005). A phase III trial of valproate has completed enrollment (Clinicaltrials.gov NCT00403104).
Talampanel (8-methyl-7H-1,3-dioxolo(2,3)benzodiazepine)
Talampanel (8-methyl-7H-1,3-dioxolo(2,3)benzodiazepine) is a noncompetitive modulator of AMPA glutamate receptors that crosses the blood–brain barrier and has prolonged SOD1G93A mouse survival. ALS functional rating scale (ALSFRS) and Tufts Quantitative Neuromuscular Examination (TQNE) scores declined at a slower rate in a 9-month phase II study of talampanel in 60 patients who had ALS .
Tamoxifen
Tamoxifen inhibits protein kinase C, and may reduce inflammation in the spinal cords of patients who have ALS . Tamoxifen extended survival in a virally induced ALS mouse model . In a phase II study of 60 patients who had ALS, tamoxifen prolonged survival .
Antiapoptosis
Minocycline
A tetracycline antibiotic, minocycline inhibits caspase activity by preventing its up-regulation, thereby decreasing motor neuron death. It also reduces glutamate-induced activation of microglia . Minocycline prolonged survival in mouse models of Huntington’s disease and FALS . In a controlled trial of minocycline (400 mg/day, n = 412), ALS functional rating scale-revised (ALSFRS-R) declined faster over 9 months in the treatment group. Strength and pulmonary function tended to decline faster, and increased mortality tended to increase .
TCH346
TCH346 (dibenz [b,f]oxepin-10-ylmethyl-prop-2-ynyl-amine, hydrogen maleate salt) prevents the apoptotic increases and the nuclear accumulation of the glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase. TCH346 (CGP 3466B) slowed disease progression in a murine model . In a controlled study of 554 subjects, TCH346 was evaluated at four different doses, with no significant differences in any outcome measures when compared with placebo .
Antioxidants
Arimoclomol
Overexpression of heat shock protein conferred protection from ischemic injury in mammalian brain . Arimoclomol, a coinducer of heat shock proteins, delayed progression of ALS in a mouse model . A dose-ranging phase II study has been completed and a phase III study is planned.
Coenzyme Q10 (CoQ10 or ubiquinone)
Mitochondrial dysfunction in ALS may be aided by coenzyme Q10 (CoQ10 or ubiquinone) . In SOD1G93A transgenic mice, low-dose CoQ10 prolonged median survival by 4.4% . Doses up to 3000 mg per day are safe and well tolerated in patients who have ALS . However, a phase III trial involving 185 people with ALS did not show any benefit over placebo .
Edaravone
The efficacy and safety of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one [MCI-186]), a free radical scavenger previously approved for treatment of acute cerebral infarction, was evaluated in patients who had ALS. Cerebrospinal fluid 3NT, a marker for oxidative stress, was reduced in a phase II trial. Decline in the ALSFRS-R score was significantly less than that in the 6 months before edaravone administration .
Melatonin
Melatonin is an amphiphilic molecule with antioxidative effects not conveyed by classic antioxidants. In SOD1G93A transgenic mice, high-dose oral melatonin extended survival. Rectal melatonin, 300 mg/day, was tolerated in a clinical safety study of 31 patients who had SALS .
Vitamin E
A study of vitamin E versus placebo in patients on riluzole yielded no difference in survival, although it showed a tendency to remain longer in the milder states of ALS with vitamin E . Five grams per day of vitamin E was well tolerated in a phase III trial. However, no significant difference in survival was noted between treatment groups .
Immunomodulatory/anti-inflammatory
Celecoxib
The anti-inflammatory celecoxib, a selective cyclooxygenase-2 inhibitor that demonstrated neuroprotective effects and prolonged longevity in SOD1G93A mice, failed to show benefit on strength measures or survival at 800 mg/day dosing in a large, randomized, placebo-controlled trial .
Creatine
Creatine has neuroprotective effects through blockade of the mitochondrial membrane pore and as an antioxidant , but failed to show benefit in two large, randomized, controlled trials .
Copaxone
Copolymer-1 (copaxone) induces a neuroprotective T cell-mediated response. ALS mice treated with copolymer-1 experienced delayed disease onset, improved motor function, and extended survival . Phase II trials of daily or biweekly injections demonstrated safety in the ALS population .
Thalidomide
Thalidomide reduced tumor necrosis factor–alpha, attenuated weight loss, and increased survival in SOD1 G93A mice . An open-label phase II trial of thalidomide is completed but the results have not been released.
Neurodegeneration
Lithium
Lithium prevents neurodegeneration by promoting autophagy through inhibition of inositol-monophosphatase; it also rescues spinal cord mitochondria and facilitates the clearance of alpha-synuclein, ubiquitin, and SOD1. It delayed disease onset and progression in G93A transgenic mice and increased survival and slowed progression in humans over 15 months, compared with controls .
Innovative approaches
Extensive ineffective clinical trials in ALS involving various subcutaneously and orally administered medications have been disappointing, which has led to novel approaches to drug delivery or nonpharmacologic forms of treatment.
Intrathecal delivery
Short half-life compounds, particularly neurotrophic factors, and larger molecules with poor penetration across the blood–brain barrier, may not achieve therapeutic concentrations in the brain and spinal cord. For this reason, intrathecal delivery of medications has been attempted in ALS. Intrathecal brain-derived neurotrophic factor in a phase I/II dose escalation study was found to be well tolerated, with spinal fluid levels directly related to dose administration . A small, double-blinded study of rhIGF-1 delivered intrathecally slowed motor deterioration on measures of total and limb Norris scales .
Gene therapy
Mechanisms for delivering gene transcripts directly to motor neuron cellular DNA by way of motor axonal retrograde transport include genetically engineered adeno-associated virus (AAV), which may be administered by intramuscular, intraperitoneal, and intravenous injection. The Bcl-xL gene, with antiexcitotoxic properties, incorporated with AAV-2 viral vector, was neuroprotective in a glutamate toxicity model in vitro , whereas intramuscularly injected GDNF- and insulin-like growth factor-AAV increased longevity in motor neuron cultures and G93A mice . AAV-2, with a coding gene for a small interference RNA to SOD1 and injected intramuscularly into G93A mice, decreased mutant SOD1 load and delayed loss of grip strength . Retrograde transport of intramuscularly injected conjugated recombinant human GDNF linked to neuronal binding fragment of tetanus toxin (tetanus toxin fragment C) produced intense immunostaining in spinal cord motor neurons, but without significant motor neuron preservation, as compared with GDNF in a neonatal rat axonotomy model . A phase I/II clinical trial involving implantation of encapsulated baby hamster kidney cells engineered to release human ciliary neurotrophic factor reported detectable cerebrospinal fluid levels of the neurotrophin in 9 of 12 study subjects, with 2 of these individuals having detectable levels up to 20 weeks postimplantation . No significant side effects were reported.
Stem cell transplant
Feasibility and safety studies of intraspinal cord implantation of autologous mesenchymal stem cells showed no convincing clinical benefits .
Cannabinoids (marijuana)
Several studies published show a significant benefit from cannabinoids, including delta-9-tetrahydrocannibinol (THC) in the SOD1 mouse model of ALS . Administration of delta-9-THC before and after the onset of ALS symptoms slowed disease progression and prolonged survival in animals, compared with untreated controls . Other trials in animal models of ALS have also shown that naturally occurring and synthetic cannabinoids slow down the progression of ALS . Another recent study showed that blocking the CB1 cannabinoid receptor extended the life span of mice that had ALS , which suggests that some abnormality within our internal cannabinoid system may be part of the underlying disease mechanisms in ALS. The cannabinoids are all 21 carbon terpenes, a chemical structure that is the same as tamoxifen. Similar to tamoxifen, cannabinoids inhibit protein kinase C, and could reduce inflammation in the spinal cord of patients who have ALS, although this remains to be studied.
Therapeutic exercise
Two studies have evaluated exercise, with some favorable response. In one, the decline of ALSFRS slowed , and the other showed improved quality of life with a trial of resistance exercise training ( Table 1 ) .
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