Accelerating Discovery


Gene therapy - For the last 15 years our laboratory had greatly contributed to define the contribution of ER stress to several neurodegenerative diseases. With the idea of enhancing the adaptive capacity of the cell, various approaches have been established to reset proteostasis by the artificially engaging of UPR gene expression programs. Gene therapy using recombinant viruses is becoming an attractive strategy to deliver active UPR components to specific brain areas. This method may also avoid the possible pleiotropic effects of systemic and chronic administration of ER stress-targeting compounds (Hetz et al., 2013 Nature Drug Discovery). Adeno-associated viruses (AAV) are the current choice to deliver therapeutic genes into the brain and spine because of the safety profile, as demonstrated in dozens of clinical trials.

Our group has extensively investigated the consequences of delivering XBP1s to various disease settings. We reported indicated that enforced expression of XBP1s using AAV injections into the spine improves motor recovery and oligodendrocyte survival in spinal cord injury models (Valenzuela et al. 2012 Cell Death Disease). This therapeutic effect was associated with an increased number of oligodendrocytes in the injured region. Our group also showed that stereotaxic injection of AAV-XBP1s into the striatum decreases mutant Huntingtin aggregation in vivo (Zuleta et al. 2012 BBRC). We also provided evidence indicating that the local delivery of AAV-XBP1s particles into the subtantia nigra has potent neuroprotective effects on a Parkinson´s disease model (Valdes, Mercado et al. 2014 PNAS). Similarly, we recently delivered AAV-XBP1 into the dorsal root ganglia and tested the impact of artificially enforcing a UPR response in peripheral nerve degeneration. Remarkably, overexpression of XBP1s accelerated axonal regeneration in the sciatic nerve in vivo, demonstrating a novel activity of the UPR in the nervous system (Onate et al. 2016 Scientific Reports). Finally, using the local administration of AAV2-XBP1s into the hippocampus of wild-type animals (rats and mice), our lab demonstrated an improvement in the basal performance in learning and memory tasks (Martinez et al. 2016 Cell Reports). Overall, these observations place XBP1 as a remarkable candidate for gene therapy to ALS since its activity may (i) attenuate ER stress levels, (ii) promote axonal repair, (iii) reduce the accumulation of protein inclusions and (iv) enhance synaptic function possibly through distinct mechanisms. In summary, all these reports suggest that strategies to attenuate ER stress levels using gene therapy may have transversal beneficial consequences on a variety of diseases and conditions that have in common altered ER proteostasis despite seemingly disparate etiologies. Our gene therapy studies in preclinical models have ben supported by the M J Fox Foundation for Parkinson Research, The Chilean Government (FONDEF) and the ALS Therapy Alliance.

International alliances for gene therapy - In addition to the scientific development, our lab has established strong networks of cooperation with key centers devoted to gene therapy and brain research that will contribute to develop our projects in all their potential. We have developed a strong partnership with Genzyme Corporation for more than seven years to generated highly pure AAVs to deliver UPR components into the CNS. Genzyme is currently equipped to produce AAVs for human use and is currently developing clinical trials in Parkinson’s disease. Strong support from UMASS is also provided, mediated by a long history of interactions with Dr. Robert Brown. Now the Gene Therapy Center at UMASS also collaborate with our group. Finally, we have developed a n strategic association with the laboratory of Drs. Patrick Aebischer and Bernard Schneider at the Brain and Mind Institute, EPFL Switzerland, a pioneering group on the development of gene therapy approaches to treat ALS and Parkinson that is also moving into clinical trials in Europe.

Drug Discovery - Pharmacological approaches are available to target protein misfolding and ER stress using synthetic several small molecules (Hetz et al., 2013 Nature Drug Discovery). We are currently developing several programs to test novel compounds to treat neurodegenerative diseases, in addition to screen for new bioactive molecules from the Chilean flora. We recently demonstrated that the disaccharide Trehalose, is a low molecular weight compounds known to stabilize protein conformation and induce autophagy, protects against ALS (Castillo et al., 2013 Autophagy). This compound has outstanding in vivo safety profiles and had been approved by the U.S. Food and Drug Administration for clinical use. In addition e have tested the impact of apoptosis inhibitors targeting the protein BAX in models of brain ischemia (Hetz et al., 2005 J Biol Chem).

We are currently testing several compounds to that selectively block specific branches of the UPR in the context of various diseases. With support from the Michael J Fox Foundation for Parkinson Research we are currently analyzing the efficacy of the PERK inhibitor GSK2606414 in models of Parkinson in collaboration with Jeff Axten at GlaxoSmithKline. In addition we are testing the effects of administrating a new compounds known as ISRIB to Parkinson and ALS models that blocks the consequences of eIF2alpha phosphorylation (collaboration Dr Peter Walter at UCSF). Finally in association with Drs Feroz Papa and Scott Oakes at UCSF we are analyzing the therapeutic potential of inhibiting IRE1 in the context of ALS. This specific project is supported by the Muscular Dystrophy Association and the CDMRP ALS Research Program (ALSRP) from the US Force. Finally, we are currently developing a large project to generate the first library of natural compounds from Chilean plants and screen them in models of protein aggregation with support of the COPEC UF Foundation.

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