THE HOMEOPROTEIN CONCEPT
Aging,
in particular aging of post-mitotic neurons, is an essential contributor to neurodegeneration development. Indeed, the majority of neurodegenerative diseases only become symptomatic in late adulthood, even when genetically driven in individuals carrying the causative mutations since birth. Neural activity is energy-consuming as illustrated by the fact that the human brain, which accounts for only 2% of total body weight, consumes 20% of the daily body energy production. Energy consumption is particularly important in neurons presenting high spiking activity and/or long projections. Among these high consuming populations, one finds midbrain dopaminergic neurons, spinal cord alpha motor neurons, retinal ganglion cells and photoreceptors which degenerate in Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Glaucoma and Age-related Macular Degeneration (AMD), respectively.
Energy (ATP) production is paralleled with that of toxic reactive oxygen species (ROS), progressively leading to heterochromatin disorganization, genomic instability and DNA breaks. These activity-associated changes are physiological and normally repaired by the cells. But with age, even in the absence of neurodegenerative pathology (healthy aging), there is a progressive degradation of the repair systems until a threshold is reached, when compensation is no longer possible, and symptoms of neuronal dysfunction appear. In neurodegenerative diseases, causative mutations and/or specific environmental factors are responsible for an early crossing of this threshold.
Homeoproteins (HPs)
A major discovery made by Prochiantz’ group is that HPs are also signaling factors transferring between cells thanks to unconventional secretion and internalization signal peptides highly conserved among the 300 existing mammalian HPs (Lee et al. 2020). Following internalization, HPs are directly addressed to the cytoplasm and nucleus of recipient cells, where they regulate several important cellular functions, including gene transcription, protein translation and epigenetic maintenance (reviewed in Di Nardo et al., 2018; 2020). Interestingly, HPs have the capacity to reverse cellular aging by restoring a more juvenile and stable epigenetic chromatin status, reducing DNA breaks and halting cell death. The first two HPs in BrainEver’s pipeline are human ENGRAILED-1 (hEN1) and human OTX2 (hOTX2) developed for the treatment of ALS, PD, Glaucoma and AMD.
Bernard Gilly PhD, has over thirty years of experience in the financial and pharmaceutical sectors, and as an entrepreneur. He co-founded BrainEver in 2015 and since served as CEO. In 2011, he created iBionext, an innovation ecosystem to develop biotech and medtech companies, in France. He is currently CEO of GenSight Biologics and a non-executive chairman of Pixium Vision,Tissium (2013), Prophesee, Chronolife (2015) and Tilak Healthcare (2016). In 2005, Bernard Gilly was Chairman and CEO of Fovea Pharmaceuticals, a biotech company he founded in 2005 and sold to Sanofi in 2009, before becoming Senior VP of the Ophthalmology Division of Sanofi until 2012. From 2000 to 2005, Bernard Gilly was a Partner at Sofinnova Partners. He founded and invested in several companies, including Fovea Pharmaceuticals (France), Sequoia Pharmaceuticals (USA), Faust Pharmaceuticals (France, now Domain Therapeutics) and Cellzome (Germany). Prior to joining Sofinnova, Bernard Gilly was President and CEO of Transgene, a company he drove from its early financing round in 1994 to its dual listing on the Nasdaq and the Nouveau Marché (Now Euronext-C) in1998, successfully raising €160m. Before Transgene, Bernard Gilly spent 6 years as VP R&D at Pasteur-Mérieux-Connaught, now Sanofi Pasteur.
Dr. Michael Shelanski is a cell biologist and neuropathologist. He received his MD and PhD degrees from the University of Chicago and trained in Neuropathology at Albert Einstein College of Medicine. Subsequently he worked in the laboratories of Nobel Laureate Marshall Nirenberg at the NIH and Jean-Pierre Changeux at the Institute Pasteur. He was Associate Professor of Neuropathology at Harvard prior to assuming the Chair of Pharmacology at NYU in 1978. In 1987 he moved to Columbia as the Delafield Professor and Chairman of the Department of Pathology and Cell Biology. Together with Dr. Richard Mayeux he founded the NIH sponsored Alzheimer’s Disease Research Center at Columbia and served as its Director for almost 25 years. He is a member of numerous advisory and editorial boards and a member of the National Academy of Medicine and of the Association of American Physicians. Dr Shelanski has served as a member of Study Sections at the NIH, the Alzheimer’s Association, the ALS Association, and the Dystonia Association. He is the Past- President of the Scientific Advisory Board of the Institut du Cerveau (Paris Brain Institute) in France.
Leonard Van den Berg, Professor of neurology and holding a chair in experimental neurology of motor neuron diseases at the University Medical Center Utrecht in the Netherlands. He is also director of the Laboratory for Neuromuscular Disease, director of the Netherlands ALS Center and chairman of the European Network to Cure ALS (ENCALS), a network of the European ALS Centers dedicated to clinical trials. A major emphasis of his research has been in ALS and other motor neuron disorders, and he has been a principal investigator on numerous drug trials in that field.
Takao Hensch, now Professor at Harvard University (USA) and University of Tokyo (JP), is one of the main academic players in the field of cerebral cortex plasticity. He has reported in a seminal paper (Science 1998) that a local GABA circuit controls experience-dependent plasticity in the developing visual system. It is in this context that he started to collaborate with Prof. Prochiantz leading to the discovery that the OTX2 homeoprotein internalized by a subpopulation of inhibitory interneuron is necessary and sufficient to open plasticity at P20 in the visual cerebral cortex and close it at P40. This study published in Cell in 2008 has opened new avenues for our understanding of how plasticity in the cerebral cortex is regulated and can be manipulated, not only in the visual system, but throughout the cortex, including regions that control mood and cognition. His work has been cited more than 20,000 times with H-index of 59 (Google scholar). He was awarded the 2016 Mortimer D. Sackler M.D. Prize for Distinguished Achievements in Developmental Psychobiology. “How Early Life Experience Shapes Brain Functions”.
Stéphane Palfi, Professor of Neurosurgery and Head of the Neurosurgery Department at Henri Mondor Medical center, Paris University (UPEC). His focus is on the development of surgical therapies for PD, Huntington disease, Tremor, Dystonia, and Psychiatric disorders. He has worked extensively around electrical neuromodulation of the brain in movement disorders, gene therapy for PD, cell grafting for Huntington and PD, as well as primate models of neurodegenerative disorders. He is a principal investigator on numerous preclinical and clinical studies and has been involved in studies of many novel agents including implanted brain devices, trophic factors GDNF, CNTF and lentiviral vectors Prosavin.
Before joining Turenne Capital in 2014, Bervin Bouani spent six years as an Asset Manager within the investment department at SHAM, an insurer specialized in healthcare companies’ risks. At SHAM, Bervin was in charge of risky assets (listed equities, Hedge Funds and private equity) and in particular was involved in the development of the private equity business (€ 30 million invested in 15 companies, including Adocia).
Benoit Barteau is Principal in the Life Sciences Department of BpifranceInvestissement. Since 2014, he has been involved in a dozen investment deals and current board member positions include Dynacure, Alentis and Igyxos. Prior, he gained experience in various biotech roles, co-discovered a vaccine candidate, developed an antibody production service.
From 2005 to 2015, Alexia was Partner and Head of Healthcare at Omnes Capital. She co-headed the management of the 26 innovative funds in venture capital.
Anne Bousseau has an extensive experience in drug development. During her 25+ years in the Sanofi-Aventis group, Anne Bousseau has held multiple senior positions all along the drug value chain, from leading a discovery group in the early days of HIV research to developing and registering oncology molecules such as cabazitaxel/ Jevtana in advanced metastatic prostate cancer. Anne Bousseau has led the Sanofi Oncology Project Direction group, in charge of the development strategy of more than 30 molecules, small molecules and biologics, starting at the preclinical stage up to registration, internally or through collaborations and alliances. During these years, a strong focus was made on translational research and the transition from Research to Development. Before that, she held different positions in the Research organization, such as AIDS Therapeutic Area leader, including target validation, lead optimization and preclinical characterization of candidates.
Hubert Méchain has a 20+ years’ experience of Biopharmaceutical development of innovative drug candidates. After a first experience as engineer for Sanofi-Synthelabo, he joined the GMP manufacturing site of Transgène (Mérieux group) specializing in immunotherapy and viral vectors. Hubert Méchain spent almost 10 years leading this site, in charge of the manufacturing of several hundreds of gene therapy clinical batches, for phase 1 to phase 3 studies, with international partners like Roche or Sanofi. He then started a consulting activity in 2015 and, took charge of the transition management of Theravectys technical operations in 2016, before joining BrainEver in 2017 to oversee the manufacturing activities.
Claire Friedel has a 17+ years of experience in the pharmaceutical industry, with various operational responsibilities in Medical Affairs for CNS drugs, focusing on the fields of Epilepsy and Parkinson Disease (Janssen-Cilag, UCB Pharma). From clinical development to new drugs launches, Claire had the opportunity to lead a wide variety of projects (clinical trials, pregnancy registry, named patient programs, web education platform & patients mobile app…). Beside drug development, she acted as Medical Education team manager in UCB China to work on the problematic of patients and physician’s education and its impact on treatment efficiency. She joined BrainEver in 2017, to lead the development projects.
Prof. Alain Prochiantz PhD, has dedicated his entire career to study, alone or in collaboration with prestigious academics (Christine Holt, Cambridge, UK; Takao Hensch, Harvard, USA; Wolfgang Wurst, Humboldt Laboratory, Munich; Michael Shelanski, Columbia University, New York…) the numerous functions of HP signaling, primarily, but not only, in the developing and adult nervous system. A former student of the EcoleNormaleSupérieure (ENS Paris),with a PhD thesis at the Faculty of Sciences René Diderot (Paris, FR) and MIT (Cambridge, USA) on the structure of plant messenger RNAs. He then joined the College de France, first as a post-doc and then as a junior group leader, where he studied the development of mesencephalic dopaminergic neurons. Following a sabbatical year at NYU School of Medicine, he started a Research unit at ENS to studythe role of HPs in the definition of neuronal shape. This led his laboratory to discover that homeoproteins can travel between cells. His work has opened up the field of vector peptides and led to several biotechnological and biomedical developments in the field of neurological diseases. The excellence of his activities has been recognized by the attribution of prestigious international (HSFPO) and European (ERC advanced) grants and several awards such as the Athena Award (2001), the Grand prix de l’INSERM (2011), and the Francqui Chair International Professorship (2019). Member of the French Academy of Sciences since 2003, he was elected at College de France in 2007 and has served as Dean of the College de France 2015 to 2019. Since 2019, Alain Prochiantz has been appointed Distinguished Guest Professor at the Shanghai Institute of Neurosciences and his heading a group research at College de France.