Cell therapy for Huntington's disease: learning from failure

International audienc

Stem Cells for Huntington's Disease (SC4HD): An International Consortium to Facilitate Stem Cell-Based Therapy for Huntington's Disease

Huntington's disease (HD) research is entering an exciting phase, with new approaches such as huntingtin lowering strategies and cell therapies on the horizon. Technological advances to direct the differentiation of stem cells to desired neural types have opened new strategies for restoring damaged neuronal circuits in HD. However, challenges remain in the implementation of cell therapy approaches for patients suffering from HD. Cell therapies, together with other invasive approaches including allele specific oligonucleotides (ASOs) and viral delivery of huntingtin-lowering agents, require direct delivery of the therapeutic agents locally into the brain or cerebrospinal fluid. Delivering substances directly into the brain is complex and presents multiple challenges, including those related to regulatory requirements, safety and efficacy, surgical instrumentation, trial design, patient profiles, and selection of suitable and sensitive primary and secondary outcomes. In addition, production of clinical grade cell-based medicinal products also requires adherence to regulatory standards with extensive quality control of the protocols and cell products across different laboratories and production centers. Currently, there is no consensus on how best to address these challenges. Here we describe the formation of Stem Cells For Huntington's Disease (SC4HD: https://www.sc4hd.org/), a network of researchers and clinicians working to develop guidance and greater standardization for the HD field for stem cell based transplantation therapy for HD with a mission to work to develop criteria and guidance for development of a neural intra-cerebral stem cell-based therapy for HD

Translating cell therapies for neurodegenerative diseases: Huntington's disease as a model disorder

There has been substantial progress in the development of regenerative medicine strategies for central nervous system disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain. Furthermore, clinical trials that incorporate principles of efficient design and disease specific outcomes are urgently needed (particularly for those undertaken in rare diseases, where relatively small cohorts are an additional limiting factor), and all processes must be adaptable in a dynamic regulatory environment. Here we set out the challenges associated with the clinical translation of cell therapy, using Huntington’s disease as a specific example, and suggest potential strategies to address these challenges. Huntington’s disease presents a clear unmet need, but, importantly, it is an autosomal dominant condition with a readily available gene test, full genetic penetrance and a wide range of associated animal models, which together mean that it is a powerful condition in which to develop principles and test experimental therapeutics. We propose that solving these challenges in Huntington’s disease would provide a road map for many other neurological conditions. This white paper represents a consensus opinion emerging from a series of meetings of the international translational platforms Stem Cells For Huntington’s Disease and the European Huntington’s Disease Network Advanced Therapies Working Group, established to identify the challenges of cell therapy, share experience, develop guidance, and highlight future directions, with the aim to expedite progress towards therapies for clinical benefit in Huntington’s disease

Stem cells for Huntington’s disease (SC4HD): an international consortium to facilitate stem cell-based therapy for Huntington’s disease

Huntington’s disease (HD) research is entering an exciting phase, with new approaches such as huntingtin lowering strategies and cell therapies on the horizon. Technological advances to direct the differentiation of stem cells to desired neural types have opened new strategies for restoring damaged neuronal circuits in HD. However, challenges remain in the implementation of cell therapy approaches for patients suffering from HD. Cell therapies, together with other invasive approaches including allele specific oligonucleotides (ASOs) and viral delivery of huntingtin-lowering agents, require direct delivery of the therapeutic agents locally into the brain or cerebrospinal fluid. Delivering substances directly into the brain is complex and presents multiple challenges, including those related to regulatory requirements, safety and efficacy, surgical instrumentation, trial design, patient profiles, and selection of suitable and sensitive primary and secondary outcomes. In addition, production of clinical grade cell-based medicinal products also requires adherence to regulatory standards with extensive quality control of the protocols and cell products across different laboratories and production centers. Currently, there is no consensus on how best to address these challenges. Here we describe the formation of Stem Cells For Huntington’s Disease (SC4HD: https://www.sc4hd.org/), a network of researchers and clinicians working to develop guidance and greater standardization for the HD field for stem cell based transplantation therapy for HD with a mission to work to develop criteria and guidance for development of a neural intra-cerebral stem cell-based therapy for HD

Nonhuman primate models of Huntington’s disease and their application in translational research

International audienceHuntington’s disease (HD) is a monogenic, autosomal dominant inherited fatal disease that affects 1 in 10,000 people worldwide. Given its unique genetic characteristics, HD would appear as one of the most straightforward neurodegenerative diseases to replicate in animal models. Indeed, mutations in the HTT gene have been used to generate a variety of animal models that display differential pathologies and have significantly increased our understanding of the pathological mechanisms of HD. However, decades of efforts have also shown the complexity of recapitulating the human condition in other species. Here we describe the three different types of models that have been generated in nonhuman primate species, stating their advantages and limitations and attempt to give a critical perspective of their translational value to test the efficacy of novel therapeutic strategies. Obtaining construct, phenotypic, and predictive validity has proven to be challenging in most animal models of human diseases. In HD in particular, it is hard to assess the predictive validity of a new therapeutic strategy when no effective “benchmark” treatment is available in the clinic. In this light, only phenotypic/face validity and construct validity are discussed

Welfare and research: automatic cognitive testing in social groups in macaques in the laboratory

Primate cognitive behavior in the laboratory has often been evaluated by housing subjects individually or isolating them and by imposing fluid or dietary restrictions to increase the subject’s motivation to work. Advances in animal welfare have significantly changed the way in which research institutions house primates in terms of space and numbers, accompanied by enrichment programs with novel objects and food that break with traditional feeding habits. Although some could potentially see these changes as a bias to previously published data, others have already proved that it is possible to obtain remarkable scientific results while offering primates a highly enriched environment. Inspired by recent publications on automated cognitive testing in social groups, our laboratory developed a special application on tactile screens, AUTOBUNTO, by which each primate learnt its own pin code to launch a single trial of its own behavioral test. This system allows testing animals on different cognitive tests while preserving social groups in their home cages. Two tactile screens can be installed at two ends of the gang cage to avoid dominance issues over screen availability. Results suggest that gang-training to touch tactile screens is quick and that completion of different cognitive tests can be acquired in a few weeks. More importantly, primates are free to work whenever they desire it instead of being imposed with a rigid testing schedule. Isolation or dietary restrictions seem unnecessary for primates to perform cognitive tests on tactile screens. Allowing access to two tactile screens is sufficient to avoid tension within the social group. In our experience, stereotypic behavior that can appear in primates housed individually or in small social groups, is absent in the presence of tactile screens, suggesting they represent a source of environmental enrichment for primates housed in the laboratory setting

Feedback control of microbubble cavitation for ultrasound-mediated blood–brain barrier disruption in non-human primates under magnetic resonance guidance

International audienc

Passive cavitation detection-based feedback control for ultrasound-mediated blood-brain barrier opening in non-human primates

Despite the progress of focused ultrasound (FUS)-mediated blood-brain barrier (BBB) disruption, neuro-inflammatory responses and the high variability of the FUS transmission through the human skull make the control of the acoustic parameters challenging. In this study, we developed a high-field (7-T) magnetic resonance (MR)-guided FUS system with a feedback control based on passive cavitation detection (PCD) to explore BBB opening in non-human primates (NHP). The sonication parameters were: 2 min duration, 500-kHz frequency, pulse length of 10 ms, and pulse repetition frequency of 5 Hz. T1-weighted MR images acquired every 5 min revealed a maximum contrast enhancement of 67% ± 15% relative to muscle after 30 min of sonication. Safe sonications were achieved in the 3 sessions using real-time PCD-based feedback control of the acoustic pressure. The high resolution anatomical images and the high temporal/spatial resolution of contrast agent diffusion provide a unique tool for studying the mechanisms of BBB disruption and drug delivery in NHP. Furthermore, the PCD-based feedback control allows repeatable safe sonication regardless of the variation of skull attenuation, allowing comparisons across animals and experimental sessions