Antibody-based therapies for Huntington's disease: current status and future directions.

The types of treatments and interventions being developed for chronic neurodegenerative disorders have expanded considerably in recent years. In addition to the variety of targets being pursued, strategies have moved from symptom management to more directed disease-modifying approaches. Among them are antibody-based therapies, which are not only being evaluated for a range of tauopathies and synucleinopathies, but are also emerging as a potential application for monogenic disorders of the central nervous system (CNS), including Huntington's disease (HD). Despite the excitement around the early trial data of anti-sense oligonucleotides (ASO) treatment for such disorders, antibody therapies may hold the key to tackling another aspect of the disease that could be critical to its pathogenesis. While gene-based methodologies are designed to lower, predominantly within cellular elements, mutant huntingtin protein (mHtt) - the genetic product of HD - the pathological protein is abundant in free forms and in several compartments including the cerebrospinal fluid, the plasma and the extracellular matrix. With accumulating evidence for the spreading and seeding capacities of mHtt, it may indeed be essential to target the protein both intracellularly and extracellularly. Therefore, free forms of mHtt not only represents an ideal target for antibodies, but one that needs to be addressed if meaningful and maximal clinical benefits are to be expected. This review explores the potential use of antibody-based therapies to treat HD, including the rationale for this approach as well as the pre-clinical data supporting it. The potential challenges that will need to be considered if such route is to be pursued clinically are also discussed.

The effects of cysteamine in a mouse model of levodopa-induced dyskinesias.

Levo-dopa (L-DOPA) has shown significant and long-lasting efficacy in the treatment of motor features characteristic of Parkinson's disease (PD). However, the effects tend to wear off at a time typically when side-effects, such as L-DOPA induced dyskinesias (LIDs), start to emerge and for which the treatment options are very limited. In recent years, we have reported on the neuroprotective and neurorestorative properties of the compounds cystamine/cysteamine in ameliorating several aspects of PD. Building on these observations, we set out to further evaluate the benefits of cysteamine on LIDs. We thus treated mice displaying LIDs with single cysteamine challenges at various doses (20, 50 and 30mg/kg) or chronically for 2 weeks using cysteamine at a dose of 30mg/kg. None of the regimens nor doses ameliorated any LID-related behavioral impairments. Mice displaying LIDs did, however, respond to a single treatment of 60mg/kg of amantadine, a drug used to clinically manage LIDs. Taken together, our results suggest that cysteamine does not induce benefits on LIDs, at least at the doses and regimen tested in our study. However, the disease-modifying effects depicted by cystamine/cysteamine, which we have shown in several reports, would strongly encourage its continued evaluation in the clinical setting.

Role of sensory activity on chemospecific populations of interneurons in the adult olfactory bulb.

The olfactory bulb (OB) retains a remarkable capacity to renew its interneuronal populations throughout the lifespan of animals. Neuronal precursors giving rise to the bulbar interneurons are generated in the subventricular zone and have to migrate long distances before reaching the OB. In the adult OB these neuronal precursors differentiate into distinct neuronal types, including GABAergic cells located in the granule cell layer and a diverse set of neurons in the glomerular layer comprising GABAergic and dopaminergic interneurons, as well as other neuronal subtypes expressing calretinin and calbindin. While the role of sensory activity in the integration and/or survival of newly generated cells in the olfactory system is well established, very little is known about how odorant-induced activity affects fate specification of newborn cells as well as survival and fate maintenance of preexisting neuronal populations generated in adulthood. The present study demonstrates that sensory deprivation diminishes not only the number of newborn cells in the OB, but also reduces the density of granule and periglomerular cells generated before nostril occlusion. It also shows that sensory activity has an important influence on the development and expression of dopaminergic, but not GABAergic, calretinin or calbindin phenotypes. Our data reveal that odorant-induced activity is important for the survival of both newborn and preexisting OB interneurons generated at adulthood and suggests that these chemospecific populations are differentially affected by sensory deprivation.