Neurological disorders pose some of the greatest challenges and areas of unmet need in medicine. Historically, nervous system conditions – such as Alzheimer’s, Parkinson’s, Multiple sclerosis (MS), and rare diseases such as Duchenne muscular dystrophy (DMD), Huntington’s and Spinal muscular atrophy (SMA) – have been the most complex and difficult to treat, affecting millions of people and their caregivers.
But recently, scientists have made significant inroads into understanding the mystery that is the brain, with better biomarkers, targets, and potential treatments for neurological diseases. Our hope is that we will soon see the kinds of transformative advances in neurology that we made in oncology in recent decades. “Neuroscience is the next great frontier in medicine,” says Casper Hoogenraad, vice president and senior fellow, Neuroscience in Genentech’s Research and Early Development organization. “I think we’re on the cusp of some major breakthroughs in this space.”
Key to those breakthroughs is joining forces with others who are studying these challenges. “Given the significant unmet need in neuroscience, and the difficulty of drug discovery and development in this space, we need better tools and more insights,” says Tom Zioncheck, Global Head Neuroscience, Ophthalmology, and Rare Diseases at Pharma Partnering. “That’s why we are especially eager to build new partnerships with academia and companies working in neuroscience.” With this mindset of openness to external innovation, there are many different types of partnerships we are pursuing in neuroscience:
BRIDGING ACADEMIA AND INDUSTRY
Many important discoveries in neuroscience happen in academic labs, but these discoveries can face barriers when transitioning from the bench into developing medicines that can reach the clinic and ultimately patients. “By partnering with academic institutes, we’re not only bringing a diversity of ideas together, but by doing so, we can bridge the translation gap from academic discovery to a clinical treatment,” says Amit Mehta*, Head of Business Development, Genentech Research and Early Development, Pharma Partnering - San Francisco.
A new and unique collaboration focuses on this approach. Scientists from Genentech and Roche are working alongside other world-class researchers and clinicians from UC San Francisco (UCSF) and UC Berkeley from the Weill Neurohub, to accelerate development of new treatments for neurological disorders.
The collaboration, called the “Alliance for Therapies in Neuroscience” or ATN, is unique in many ways. It fosters greater teamwork not just between industry and academia, but also internally, where our research and development groups at Roche and Genentech usually operate independently. But in neuroscience, we need to join forces. “The more we learn from each other, the more likely it is that we can advance the field, says Azad Bonni, global head of Neuroscience and Rare Diseases in Roche’s Pharma Research and Early Development organization. “A great idea is a great idea whether it comes from a scientist at Genentech, Roche or academia. Working together ensures that we can ultimately do more for patients.”
The ATN will initially fund projects focused on neurodegeneration, therapies based on CRISPR technology (editing of DNA sequences), functional genomics in human brain cells, and sleep mechanisms and circuits.
“This partnership will help us better understand disease pathologies, discover novel targets, generate new preclinical models and develop novel translatable biomarkers that will further accelerate the development of therapeutics for CNS disorders,” says Hoogenraad.
The collaboration will also give our scientists more opportunities to leverage cutting-edge technologies like next-generation neuroimaging, CRISPR gene editing, artificial intelligence and high-end computing.
“Jennifer Doudna, who won the Nobel Prize for her work in CRISPR gene editing, will be one of the leading academics that will be involved in this collaboration,” says Mehta. “It’s very exciting.”
Almost a decade ago, our colleagues at Roche believed in the potential of targeting RNA with small molecules as a treatment for neurological disorders, and pursued a partnership with PTC Therapeutics and the Spinal Muscular Atrophy (SMA) Foundation. This collaboration has already proven successful in developing a much-needed treatment for patients with SMA.
Such treatments, known as RNA splicing modulators, are therapeutics that don’t directly target proteins, but are instead designed to bind to RNA molecules and change the expression of specific proteins – either blocking a protein’s production or modifying the type of protein being made. “Since RNA modulators don’t target proteins, the druggability of the protein itself is irrelevant,” says John Moffat, Genentech senior scientist, Biochemical & Cellular Pharmacology. “That makes these therapeutics very versatile.”
RNA splicing is the process where a newly made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). The normal process of RNA splicing removes sections of RNA that do not code for protein, allowing the coding sections to be stitched together. When this process occurs incorrectly, the resulting protein can be dysfunctional. RNA mis-splicing can affect protein expression, which can lead to a wide array of diseases including cancer and neurodegenerative diseases.
Learn more about RNA Splicing Modulators.
Two of our recent partnerships focus on this new approach. One is in partnership with Skyhawk Therapeutics, where scientists at Genentech are leveraging Skyhawk’s unique expertise in splicing biology to help identify small-molecule modulators that can bind RNA and modify its splicing. This work will help to pursue challenging targets in neurological disease with the ease of small-molecule oral treatments.
“The development of RNA splicing modulators could significantly widen our ability to hit previously “undruggable” disease targets and potentially offer new treatment options for patients,” said Tapan Maniar, business development site head South San Francisco for Research Technologies, Pharma Partnering.
Another partnership, between Genentech and Atalanta Therapeutics, will focus on the development of RNAi (RNA interference) therapeutics for multiple targets for neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease.
Atalanta’s novel RNA interference oligonucleotide technology called branched siRNA has shown strong potential in silencing problematic gene expression in the central nervous system. One problem for scientists using small interfering RNAs (siRNAs) is that they don’t distribute throughout the brain. Atalanta has developed technology to modify these siRNAs to allow them to get to where they need to go in the brain. The technology can be applied across multiple neurodegenerative diseases. One of the founders of Atalanta is Craig Mello, who received a Nobel Prize for his discovery of RNA interference.
“The partnership with Atalanta gives us access to an RNAi platform that has shown remarkable brain distribution, which has always been a challenge with oligonucleotides. By working together, we will use this exciting technology to hopefully move more quickly to address the numerous neurodegenerative diseases in urgent need of treatments,” says Mehta.
One of the neuroscience partnership areas where Roche is leading the way is in the use of digital technologies to enhance patient experience and outcomes. This includes the use of technologies like virtual reality (VR) to develop solutions in the broad area of digital therapeutics (DTx). It also includes technologies like wearable devices, apps, sensors and services that may help manage or enhance the treatment of conditions either alone or in conjunction with traditional medicine-based treatment. Such digital interventions could combine both hardware and software and have been shown to be effective in clinical studies to monitor disease progression.
“The neuroscience field uses the phrase, ‘Pills don’t teach skills,’” says Gregg Talbert, Senior Vice President, Global Head Personalized Health Care and Digital Partnering at Pharma Partnering. Digital tools can help individuals with behavioral therapy. “As much as you can affect certain disease characteristics and symptoms from traditional pharmaceutical products, skills learning is often a part of managing conditions,” he says.
With digital tools, Roche is collaborating with the Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) with the aim to hopefully develop new, more reliable, informative and meaningful methods to assess disease progression in MS and other neurological diseases with new digital measurements. People with MS often feel their disease progressing over time but it is not always easy to detect and keep track of subtle changes in their cognition and motor function. Leveraging digital tools to measure and assess disease progression better could ultimately empower them with more information about their disease and help health care providers recognize disease progression faster.
Through the collaboration, RC2NB plans to incorporate elements of one of Roche’s technologies into their methods for assessing the progression of MS. The data collected through active and passive monitoring can then be analyzed using advanced computational methods to hopefully generate a more comprehensive picture of the disease.
Roche is also collaborating with HARMAN, a subsidiary of Samsung Electronics, to develop a digital therapeutic technology for individuals with autism, or autism spectrum disorder (ASD). This neurological disorder is characterized by challenges with social skills, repetitive behaviors, speech and non-verbal communication. Patients undergo regular behavioral therapy to help them learn new skills to better cope in the real world.
This partnership aims to use virtual reality (VR) to deliver the “therapeutic” component that would hopefully help improve social communication skills. The VR headset can be used at home to “practice” interactive scenarios. The data gathered by active and passive monitoring can then be shared with the healthcare provider and therapist to inform about a patient's progress.
Roche and HARMAN’s partnership also seeks to expand the platform for development of other digital health products across multiple therapeutic areas.
A NEW FUTURE FOR NEUROSCIENCE
All of these partnerships are looking toward fundamentally changing the landscape of neuroscience for the future. “While we know that neuroscience research presents challenges because of significant investment and high failure rates, we are using partnerships to develop technologies and expertise to overcome these challenges,” says Zioncheck. “We see the significant unmet need and the opportunity to help patients – and we don’t give up just because it’s hard.”
Our aim is to create a future in which neurological disorders no longer limit human potential – to preserve what makes people who they are. “Understanding neuroscience is an integral part of our future,” says Hoogenraad. “We are driven by the idea that the rigorous pursuit of science can unlock our understanding of neurological disorders and help transform the lives of people facing serious and life-threatening diseases.”
*While Amit was an employee at the time this article was published, he has since left Genentech.