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Huntington's Disease: Developing a Preventative Drug

Huntington's disease (HD) is an inherited autosomal dominant disorder of the central nervous system. This polyglutamine disorder is passed from parent to progeny with a 50 percent chance of inheritance. Normal individuals have 7 to 34 CAG repeats in the Huntingtin (Htt) gene which encode glutamine amino acids in the Htt protein. The CAG repeats are expanded and unstable in HD patients, with repeat lengths inversely correlating with age of disease onset. Repeat lengths greater than 40 glutamines invariably cause HD, and repeats of greater than 100 glutamines typically cause juvenile onset. HD is a neurodegenerative disease characterized by movement disorder, dementia, and psychiatric disturbance which typically develops in the fourth or fifth decade of life with a disease duration of 10 to 25 years. Thirty thousand Americans have HD at an annual cost to American society of $2.5 billion with another 250,000 individuals at risk to inherit the disease. There is no cure or preventative for HD. Theories of HD pathogenesis include excitotoxicity, inappropriate apoptosis, mitochondrial dysfunction, and transcriptional dysregulation. Present treatment of HD is management of symptoms with currently marketed therapeutics, therefore there is great interest in the development of an effective therapeutic for HD. Numerous published investigations have shown effectiveness in preclinical studies of a significant number of compounds but few if any results have translated to efficacy in humans. Human HD therapeutics based on the underlying pathogenic mechanisms of HD have great promise in preventing or stopping progression of the disease.

Background and Significance

Although Huntington's disease (HD) was reported in the literature over a century ago, no therapy exists to slow or stop the progress of this disease. Much, however, has been learned about the mechanisms of neuropathogenesis of HD. The discovery of the Huntingtin (Htt) gene in 1993 (HD Collaborative Research Group, 1993) and that expanded CAG repeats in the gene resulting in glutamine repeats in the Htt protein are the primary cause of HD [1] were major breakthroughs that have allowed for the delineation of the extensive mechanisms of pathogenesis of HD.

HD is an inherited autosomal dominant disorder of the central nervous system. The disease is passed from parent to progeny with a 50 percent chance of inheritance with one parent having the disease. Thirty thousand Americans have HD with another 250,000 at risk to inherit the disease [2]. HD is molecularly defined as a polyglutamine disorder. Normal individuals have CAG repeat lengths producing 7 to 34 glutamines, however, the CAG repeat number is expanded and unstable in HD patients, showing repeat lengths inversely correlating with age of disease onset. Repeat lengths greater than 40 glutamines invariably cause HD, and repeats of greater than 100 glutamines typically cause juvenile onset [3].

Theories of HD Neuropathogenesis. The exact mechanism by which neurons die as a result of mutant Huntington in HD remains unknown. The discovery of the HD gene, and more recently, the development of transgenic mouse, fly, and worm models sets the stage for the discovery of actual pathogenic mechanisms of mHtt and the manner in which mHtt is involved in the process. Far from arriving at a unifying mechanism, there is instead robust evidence that multiple pathologic mechanisms occur in HD [2].

Mitochrondrial dysfunction and oxidative stress. Multiple studies have provided evidence for the involvement of mitochondrial dysfunction and increased oxidative stress in HD [4]. There is a reduction in the utilization of glucose in striatal cells both in humans and transgenic mice prior to cell death [5, 6], along with a reduction in activity of many mitochondrial complexes [7, 8]. Lactate levels are increased in striatum and cortex, with the increase correlating with increase CAG repeat size [9].

Higher levels of markers of oxidative stress are observed in human and transgenic mouse brain and serum, such as DNA oxidative changes and strand breakage and deletions of DNA in mitochondria [10]. While derangements in energy metabolism are well documented in HD, it is still unclear whether these defects are a cause of the disease or a consequence [2].

Transcriptional dysregulation. Large polyQ tracks are a causative feature of mHtt. A polyQ track is a common feature of transcription factors. Mutant Htt has an aberrant localization in the nucleus and different protein-protein interaction characteristics, therefore mHtt may act to sequester polyQ containing transcription factors leading to aberrant transcription and cell death [11]. Recent studies have shown differences in gene transcription in transgenic HD mouse models indicating that transcription repression is the main result [12-15]. Many of the transcription factors deregulated in HD effect histone acetylation, a process which alters transcription through covalent modification of chromatin [16-18].

The ubiquitin-proteosome system, autophagy, and aggregation of mHtt. Transglutaminase modification has been implicated in the aggregation of mHtt [19]. There is significant evidence for increased transglutaminase expression in HD [20-22] and the role of transglutaminase in HD pathogenesis is now fairly well accepted but it is unclear whether it is a cause or an effect.

The ubiquitin-proteosome (UPS) system and autophagy play a role in clearing aberrant and misfolded proteins and organelles including these proteins. However, proteins containing large tracks of polyQ, such as mHtt, are not very effectively degraded by the UPS system because of difficulty in cleaving within the mutant Htt sequence [23]. There have been reports of improved survival of neurons with mHtt aggregates [24, 25]. Therefore, it is unclear whether mHtt aggregates are protective or toxic and whether they are coincidental or have an additive effect with other HD pathogenic mechanisms.

Apoptosis. There is much evidence to support a role of caspases and apoptosis in the pathology of HD. In apoptotic-induced cell death, signaling cascades activate multiple proteases that destroy proteins and concurrently activate genes involved in programmed cell death [26]. The primary players of the apoptotic cascade are the caspase enzymes. Three initiator caspases 3, 6, and 7 have been implicated in HD [27]. The specific participation of caspases 3 and 6 is detailed in section B.1. Stack and Ferrante [28] indicate that given the apoptotic activity involved in HD, pharmacologic inhibition of proteins involved in various levels of the signaling cascade may represent a potential beneficial therapeutic strategy to treat HD.

Excitotoxicity. Increased levels of glutamatergic input to the striatum is hypothesized to contribute to death of cells in this part of the brain in HD. Evidence supporting this view first came from observations that injections of excitatory amino acids into the striatum of rodents led to neuronal death with characteristics similar to HD [29]. Increases in striatal glutamate in the brains of HD patients [30] as well as changes in presynaptic glutamate receptors in the R6/2 murine model [12] lend additional support to the role of excitotoxicity in HD. Although excitotoxicity has become an accepted mechanism of pathogenesis of HD, there is no rationale for the observation that the hippocampus, cortex, and cerebellum contain similar or higher levels of glutamate receptors yet there is striking selective loss of striatal neurons in HD [2].

Huntington's Disease Therapeutic Drug Development. Currently there exists no therapy that can halt or diminish the progress of HD. With increased understanding of the many pathogenic mechanisms of HD, therapeutic strategies have attempted to target specific aspects of these mechanisms. There have been many encouraging reports from preclinical studies. However, these promising therapies have not progressed to clinical trials. This disparity between the effectiveness of drugs in animal model systems and in humans may be due to underpowered clinical trials, preventing a comparison of therapeutic efficacy between animal model systems and humans [28]. Alternatively, optimal therapeutic dosing may be underestimated. The reliance on human equivalent dose extrapolation measurements derived from body surface area criteria in animals may be deficient (U.S. Department of Health and Human Services, FDA). Although the animal model systems may well be predictive of efficacy in humans, extrapolation to an efficacious dose in humans remains problematic [28].

Clinical Management of HD. In the absence of an effective therapeutic for HD, existing care for HD patients focuses primarily on symptom management. A number of drugs on the market for other indications are being used to treat the motor and behavioral changes that occur with HD. Amantadine [31] and Memantine [32], NMDA antagonists, have been used to treat chorea. Haloperidol has been used in an attempt to address dystonia and psychosis [33]. Recent data on Tetrabenezine, an inhibitor of dopamine release, shows improvement in chorea in ambulatory patients (Huntington Study Group, 2006). Clinical practice employs antipsychotic agents for management of depression, anxiety, and other psychiatric disturbances. These include serotonin uptake inhibitors, Sertraline and Fluoxetine and/or benzodiazepines such as Clonazepam, Diazepam, Risperidone or Sulpiride [34]. There is no evidence that any given antipsychotic drug is any better than another in the management of symptoms. There is a great need to advance the treatment of HD from a paradigm of symptom management to a level where the disease pathology can be targeted directly at a molecular level.

Therapeutic Candidates

Mitochrondrial dysfunction and oxidative stress. With oxidative stress a result of mitochondrial dysfunction, several preclinical antioxidant strategies have been implemented with some success. Creatine, while produced endogenously and also obtained from the diet, has shown antioxidant capacity, buffers intracellular energy reserves, stabilizes intracellular calcium, and inhibits activation of the mitochondrial transition pore [35]. Several preclinical studies have shown neuroprotective properties of creatine [36-42]. Another antioxidant that has shown preclinical efficacy in multiple HD animal model systems is coenzyme Q10 (CoQ) or ubiquinone [43-45]. CoQ is a lipid-soluble benzoquinone that provides antioxidant properties when reduced to ubiquinol or through induced increase in α-tocopherol [46].

Therapies targeting other aspects of mitochondrial dysfunction include n-3 fatty acid eicosapentaenoic acid (EPA) which possesses hypo-triglyceridemic activity acting as a mitochondrial proliferator [47]. Using a derivative of EPA , ethyl-EPA, the R6/1 murine model showed significant improvements in multiple motor and behavioral abnormalities [48]. A 6-month clinical trial with ethyl-EPA demonstrated significant improvement in orofacial aspects of Unified Huntington's Disease Rating Scales (UHDRS) [49]. However, recently ethyl-EPA treatment of HD patients was reported to have no effect on UHDRS [50].

The antihistamine Dimebolin (also known as Dimebon) is an orally active small molecule that appears to affect the mitochondrial permeability transition pore, preventing the calcium-induced opening of the pore [51]. A Phase II clinical trial on the safety and tolerability of Dimebolin in HD patients has been completed.

Transcriptional dysregulation. The transcriptional repression observed in HD likely results from alterations in chromatin packaging associated with epigenetic modifications of histone proteins [28]. Pharmacological targeting of histone methylation and acetylation status may provide some neuroprotection in HD. Several preclinical trials with compounds, sodium butyrate or suberoylanilide hydroxamic acid (SAHA), directed toward altered histone profiles in HD have been performed [52-54].

Two compounds which act directly with DNA to influence transcription activity are Mithramycin and Chromomycin. These compounds bind to guanine-cytosine-rich regions within gene promoters, displacing transcriptional elements that activate or repress transcription [55]. These compounds have shown improvements in preclinical models of HD [56, 57].

The ubiquitin-proteosome system, autophagy, and aggregation of mHtt. The degradation of mHtt is another potential therapeutic target. Protein turn over is a normal process which promotes healthy cells. Altered proteolysis may cause persistence of denatured or misfolded proteins contributing to cellular dysfunction. There are two main pathways for proteolysis in neurons, ubiquitin-proteosomal (UPS) pathway and lysosomal pathway. Proteins destined for the UPS pathway must first be ubiquinated.

Degradation of proteins and organelles in bulk is accomplished through the lysosomal pathway, in a process called autophagy [58]. In this process, cellular components destined for degradation are enveloped in double membrane vesicles which fuse with lysosomes and the contents are degraded by hydrolytic lysosomal enzymes. While the process of autophagy is not fully understood, phosphorylation and dephosphorylation of mammalian target of rapamycin (mTOR) clearly plays a role in autophagy [59]. Compounds which interact with mTOR to promote autophagy may prove beneficial in HD [28]. Preclinical studies have shown promise with anti-mTOR compounds [60, 61].

Other studies of potential inducers of autophagy independent of mTOR have identified lithium as an effector. Lithium seems to increase clearance of mHtt and reduce mHtt induced cell death [62].

Reduction of mHtt aggregation may also be of therapeutic benefit. In this regard, Cystamine may hold promise with antioxidant properties and inhibitory transglutaminase activity [63]. Transglutaminase activity is implicated in mHtt aggregation. Preclinical trials have shown promise with Cystamine [64-66] and also in clinical trials [67, 68]. The molecules being tested as SBIM candidates for mHtt will also be examined as inhibitors of polyQ aggregation in Prof. Andersen's laboratory.

Apoptosis. Among the antiapoptotic drug candidates, the tetracycline antibiotic drug Minocycline immerged as a drug with the most HD potential. Minocycline mediates antiapoptotic activity through its effect on caspase 1 and 3. Also, it seems to attenuate release of cytochrome C from mitochondria [69, 70]. Promising preclinical studies were initiated [69-72] and lead to pilot clinical trials assessing safety and tolerability in humans (Huntington Study Group, 2004). However, no relevant differences in cognition assessed by UHDRS have been observed [73-75].

Aside from Minocycline-mediated caspase inhibition, recently another drug, M826 a pyrazinone mono-amide with reversible caspase 3 inhibitor activity has shown promise in preclinical trials [76]. However, this drug has challenges because of solubility and lack of blood brain barrier penetration and a global inhibitory affect on caspase 3.

Excitotoxicity. Glutamate excitotoxicity is also believed to play a role in HD. Compounds that counter excess glutamate may therefore be candidates for HD therapy. Riluzole is an FDA approved compound with potent antiglutamate activity, attenuating glutamate release through inhibition of voltage-dependent sodium channels [77]. Significant neuroprotection was observed in preclinical model systems [78-82]. These promising preclinical studies prompted a number of clinical trials. In a 6-week safety and tolerability trial with Riluzole assessing motor performance and brain lactate levels, Riluzole was found safe with non-significant trend toward lower basal ganglia lactate levels [83]. Analysis of motor function demonstrated a decrease in chorea as assessed with UHDRS. Additional clinical evaluation also indicated efficacy of Riluzole (Huntington Study Group, 2003; [84]. Interestingly other glutamatergic agents, Amantadine and Memantine have shown mixed results [85-88]. In addition, all of these drugs show significant side effects [28].

Other therapeutic strategies. There are other potential HD therapeutic approaches that warrant mentioning. One of the most promising is RNA interference (RNAi) mediated by micro RNA (miRNA) and short interfering RNA (siRNA) which targets homologous RNA. Targeting and down regulating mHtt RNA in several preclinical studies have shown promise [89, 90]. However, there are significant challenges to the development of RNAi to treat HD. While intracerebral infusion of AAV containing RNAi may be suitable in animal studies, safe and effective delivery of RNAi molecules to humans where RNAi needs to be delivered to all important target cells is a real challenge with no current technology capable of this feat.

Transplantation of neural tissue or stem cells represents another therapeutic approach. Several preclinical studies of transplantation showed promise including improved functional capacity [91-94]. In a study with three HD patients with bilateral transplantation of fetal striatal tissue into the caudate and putamen, the transplantation was successful and produced improved motor behavior, as assess by UHDRS [95]. In a subsequent safety and tolerability trial several patients showed marked improvement in UHDRS score but complications in the use of immunosuppressants making analysis impossible [96]. Additional cross species trials have been performed using porcine fetal tissue but complications with immunosuppression and xenograft rejection indicates the difficulty in treating human HD with clinical striatal transplants [97].

Therapeutic Outlook. The development of effective therapeutic agents for HD will require extensive preclinical and clinical validation to provide necessary safety, tolerability and efficacy for clinical use. The development of genetic model systems has greatly aided in drug development and will continue to do so in the future. It is important, however, to understand the challenges of predicting the transference of success from preclinical model systems to humans. Importantly, data from preclinical trials using multiple models is likely to be most informative when assessing benefit for humans [28]. We address this concept by developing a specialized HD model in Drosophila in addition to utilizing an established mouse model to confirm the activity of our candidate SBIM HD therapeutic molecules in vivo.

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