Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a debilitating disease with varied etiology. ALS is characterized by rapidly progressive weakness, muscle atrophy and fasciculations, muscle spasticity, difficulty speaking (i.e., dysarthria), difficulty swallowing (i.e., dysphagia) and difficulty breathing (i.e., dyspnea). Worldwide, ALS kills about 100,000 yearly, with 125,000 new ALS diagnoses yearly.
ALS causes muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel sphincters and the muscles responsible for eye movement are usually spared until the terminal stages of the disease. Most patients do not lose cognitive function, but about 5% develop frontotemporal dementia.
The precise cause of ALS is still unknown, but mutations in the gene that produces the Cu/Zn superoxide dismutase (SOD1) enzyme are present in approximately 20% of familial ALS cases. SOD1 is a powerful antioxidant that protects the body from damage caused by the toxic free radical superoxide, which is generated in the mitochondria. To date, over 110 different mutations in SOD1 have been linked with ALS. Failure of defenses against oxidative stress upregulates programmed cell death (apoptosis). An accumulation of free radicals due to faulty SOD1 functioning may thus lead to motor neuron degeneration. However, it is also possible that mutant SOD1 induces toxicity by a gain of function. For example, in some mutant SOD1 mice, mutant SOD1 aggregates (misfolded protein deposits) were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration. This observation is consistent with a model where mutant SOD1 aggregates help disrupt cellular functions by damaging mitochondria, proteasomes or protein folding chaperones. In humans, SOD1 mutations cause only 2% of total ALS cases, and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. For non-familial cases (around 90% of ALS cases), the disease may be triggered by head trauma, military service, or participation in contact sports.
Riluzole (RILUTEK®) is the only drug currently approved to treat ALS, but its therapeutic success is limited. Riluzole slows down disease progression by about 3-9 months, prolongs survival by several months, and delays the need for ventilation support. However, the drug does not reverse the damage already done to motor neurons, and may cause liver damage in about 10% of the patients.
In one aspect, development of effective ALS treatments may be hampered by a combination of low drug bioavailability and disease-driven pharmacoresistance, which limits CNS drug penetration and ultimately compromises drug efficacy.
Pharmacoresistance is mediated for example by the ATP-binding cassette (“ABC”) drug efflux transporters. ABC transporters are transmembrane proteins that utilize the energy of adenosine triphosphate (ATP) hydrolysis to carry out biological processes, including translocation of substrates (e.g., metabolites, lipids, sterols and drugs) across extra- and intracellular membranes. ABC transporters play a crucial role in the development of multidrug resistance (MDR), whereby patients eventually develop resistance not only to the drug they are taking but also to additional types of drugs to which they had not been exposed. MDR is linked by the increased cellular excretion of the drug by ABC transporters. ABC transporter families include ABCB1 (also known as P-glycoprotein, P-gp or MDR1), which transports organic cationic compounds or neutral compounds; MRP, which transports organic anionic compounds; and ABCG2 (also known as breast cancer resistance protein or BCRP), which confers resistance to Topoisomerase I or II inhibitors such as topotecan, irinotecan, and doxorubicin. ABC transporters are predominantly located in the lumen of endothelial cells of the blood-brain barrier, where they limit the entry of neurotoxins into the CNS. Unfortunately, clinical trials in cancer patients to which ABC transporter inhibitors were co-administered, with the objective of increasing the anticancer drug efficacy, had ultimately disappointing outcomes (Sharom, 2008, Pharmacogenomics 9(1):105-127; Szakacs et al., 2006, Nat. Rev. Drug Discov. 5:219-234).
There is a need in the art for novel methods of treating neurodegenerative diseases in a mammal in need thereof. The present invention fulfills this need.