Disease-modifying therapy for AD
The histopathological evidence of abnormal protein deposition has prompted genetic and pharmacological interventions that inhibit the accumulation of causative molecules in various neurodegenerative diseases. One of the most-studied targets is amyloid plaques in AD, because the majority of disease-modifying therapies for AD have been developed on the basis of the amyloid cascade hypothesis. For instance, active immunization with Aβ vaccine reduced amyloid plaque burden and improved behavioral phenotypes in a transgenic mouse model carrying mutant APP. Similarly, passive immunization using anti-Aβ antibodies inhibits the formation of plaques and ameliorates behavior deficits. Therapies targeting β- and γ-secretases that produce the Aβ peptide via cleavage of APP have also been developed, and some of them suppress the production of toxic Aβ peptides in animal models of AD. In addition to Aβ oligomers, tau, the major component of neurofibrillary tangles, is also a critical target of therapy development for AD. It is commonly held that, following Aβ deposition, tau is hyperphosphorylated and forms neurofibrillary tangles in vulnerable neurons. Suppression of tau phosphorylation by lithium, an inhibitor of glycogen synthase kinase 3β, mitigates neurodegeneration and improves cognitive function in an animal model of AD. Other candidates that dampen neurodegeneration in AD include microtubule stabilizers, antioxidants, mitochondrial protectors, immune response modulators and autophagy inducers.
Nevertheless, none of the agents thus far mentioned has demonstrated beneficial effects in clinical trials, even though they ameliorate histopathological and behavioral findings in AD model animals. Aβ vaccine AN1792, which contains a synthetic form of the Aβ42 peptide, was the first immunotherapy tested in clinical trials. Although anti-Aβ antibodies were produced in a subset of AD patients treated, the phase 2a study of the vaccine was discontinued due to serious adverse events, including meningoencephalitis and leukoencephalopathy. Intriguingly, AN1792 reduces the amyloid plaque burden in the brains of AD patients compared with those of unvaccinated cases, suggesting that the active immunization ameliorates AD pathology in humans. However, the effects of this therapy on cognitive function or survival were not clearly shown in the phase 2a trial or in a long-term follow-up of a phase 1 study.[14, 16] Passive immunization with anti-Aβ monoclonal antibodies, bapineuzumab and solanezumab, has also been tested in humans. Primary endpoints, both cognitive and functional, were not met in the phase 3 trials of either drug, although solanezumab showed small, but statistically significant effects on some cognitive functions and independent activity of daily living in patients with mild AD.
Moreover, even with passive immunization, there can be vasogenic edema and microhemorrhage that depend, in part, on ApoE allele status, a genetic risk factor of AD. Neither other Aβ aggregation inhibitors nor γ-secretase modulators showed benefits over placebo in clinical trials.
Although various factors appear to underlie the discrepancies between the histopathological and functional outcomes in clinical trials of Aβ vaccine, several studies strongly indicate the possibility that inhibition of Aβ aggregation, the upstream event in the pathological process, is not sufficient for suppressing disease progression at a symptomatic stage of AD. This view is supported by the observation that Aβ aggregation as detected with positron emission tomography using Pittsburgh Compound B and the decreased Aβ42 in cerebrospinal fluid antedated the onset of cognitive deficits in AD patients. Hippocampal atrophy is also detectable in magnetic resonance imaging (MRI) before the manifestation of clinical symptoms in familial cases of AD, suggesting that molecular changes are already extensive when the disease is diagnosed. In addition, it is supposed that immunotherapies are most effective when they are initiated at early stages of the disease in animal models of AD. Together, these observations suggest that current disease-modifying therapies for AD have limited effects on disease progression in symptomatic patients, in whom various molecular events downstream to Aβ aggregation overwhelm the neuroprotection by the interventions.
Disease-modifying therapy for polyglutamine diseases
In view of their monogenic natures, polyglutamine diseases are thought to be a pragmatic model in the development of disease-modifying therapies for neurodegenerative disorders. Genetic modulation inhibiting the nuclear localization of polyglutamine-expanded protein results in marked suppression of disease manifestation in mouse models of polyglutamine diseases, suggesting that inhibition of abnormal protein accumulation is a fundamental strategy to slow pathophysiological progression in polyglutamine diseases. This hypothesis has been rigorously tested in SBMA, a polyglutamine disease characterized by progressive loss of lower motor neurons within the spinal anterior horn and brainstem. SBMA is caused by the expansion of a CAG repeat in the gene coding androgen receptor (AR), and exclusively affects males. Leuprorelin, a potent luteinizing hormone-releasing hormone (LHRH) analog, has been shown to inhibit the testosterone-dependent nuclear accumulation of the polyglutamine-expanded AR, resulting in a marked improvement of neuromuscular phenotypes seen in the AR-97Q mouse, a transgenic animal model of SBMA. In a phase 2 clinical trial, 12 months treatment with leuprorelin significantly diminished the serum level of creatine kinase, and suppressed the nuclear accumulation of the polyglutamine-expanded AR in the scrotal skin. Of note is the observation that the frequency of neurons bearing pathogenic AR in the anterior horn and brainstem of an autopsied patient, who received leuprorelin for 2 years, was less than in non-treated SBMA patients. Nevertheless, no definite effects on motor functional scores were observed in a 48-week randomized placebo-controlled multicenter clinical trial, although there was improvement of swallowing function, measured as the pharyngeal barium residue in videofluorography in a subgroup of patients whose disease duration was <10 years, as well as a decrease in AR accumulation in scrotal skin biopsies and serum levels of creatine kinase. Also, a phase 2 clinical trial of dutasteride, a 5-α-reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone, did not demonstrate effectiveness. Although the results of these studies are inconclusive, their findings do not exclude the possibility that ligand-targeted therapies slow the progression of SBMA. Given the strong evidence shown in basic studies, this hypothesis needs to be further verified in clinical trials with a rigorous and efficient design.