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    CRISPR: the gene editing revolution is beginning

    December, 18th 2023

    As part of its mission to encourage and support talents with an innovative spirit to pursue scientific questions with disruptive potential, Pioneer Science is proud to announce a partnership with the Innovative Genomics Institute (IGI). Founded by the American biochemist Jennifer Doudna, winner of the 2020 Nobel Prize in Chemistry, and linked to the University of California Berkeley, IGI is a leader in research with the CRISPR gene editing technique, which has immense potential both in medicine and in other areas.

    The technique opens the field of gene editing and paves the way for the cure of previously incurable genetic diseases, such as sickle cell anemia, cystic fibrosis and others.

    Aware of the importance and revolutionary potential of this research, Pioneer Science committed to an investment of US$4 million in the partnership, which involves the exchange of researchers, meetings to discuss new fronts of clinical research and setting up laboratories to develop treatments for genetic-based conditions, neurodegenerative diseases and cancer. One of the partnership achievements will be a range of Brazilian researchers who will master the technique and be able to develop the methods in the country.

    Between October 17th and 21st, Pioneer Science received researchers and executives from IGI in Rio de Janeiro for visits to IDOR and Rede D’Or hospitals and participation in seminars and debates with Brazilian researchers. Brazilian postdocs Bruno Solano and Thyago Leal-Calvo, fellows supported by the initiative, were also present. They have already been working and being trained at IGI since the beginning of the year.

    Bruno is an cell therapy specialized MD linked to IDOR and Bahia state’s Fiocruz in Brazil. His project studies alternatives to reduce the costs of using gene therapy to treat sickle cell anemia, a genetic disease that leads to serious complications and is highly prevalent in the black population.

    Thyago has a doctorate in molecular biology and, in his project, seeks to apply the CRISPR-Cas technique to edit the epigenetic mechanisms that regulate gene expression, in order to stop the progression of Alzheimer’s disease, associated with a decline in cognitive function and memory.

    J. Doudna gave an interview to Brazilian newspaper “O Globo” about the partnership and the next steps for implementing the technique in treating diseases. On this page, we revisit that interview and expand it with the participation of fellows Bruno and Thyago.

    Ciência Pioneira: Bruno, Thyago, how do you feel about being part of this initiative, working directly with Dr. Doudna and her team, and what are your expectations for this partnership between IGI and Ciência Pioneira?

    Thyago: Firstly, I feel flattered and grateful for the opportunity! It’s a huge challenge, but we are committed. Jennifer Doudna is an incredible scientist with a worldview centered on reducing inequalities, which is commendable. Being part of a scientific community such as IGI is both stimulating and challenging, particularly due to the Institute’s mission, with focus on innovative, high-level science with applicability, something that is fully aligned with Pioneer Science. I hope that this partnership will help to promote new studies using CRISPR in Brazil, especially translational ones, according to our needs and socioeconomic context. Furthermore, I hope the partnership serves as an inspiration for future scientists.

    Bruno: It is an honor and at the same time a great responsibility; that’s why we take this opportunity very seriously. IGI is a global reference and is led by Jennifer Doudna, who has a very inspiring career in science and who made discoveries that impacted the entire world, as we have all heard. But something that stands out is IGI’s commitment to disseminating and increasing access to CRISPR technology, which I believe aligns very well with the Pioneer Science proposal.

    Dr. Doudna, you have two Brazilian scientists at IGI/Berkeley now working on CRISPR applications. One is in sickle-cell research, the other is in neurodegenerative diseases. How much progress did you obtain so far in these fields?

    We’re so happy to have them at the IGI! There has been amazing progress on sickle cell disease. The mutation that causes sickle cell disease is a single letter mutation in the genetic code, so it’s well understood and the ways we can address it with CRISPR genome editing are relatively straightforward. There is still much more we can do to make the therapy more efficient, easier for patients, and more affordable, which is what we are focusing on.

    Neurodegenerative diseases are more challenging for a number of reasons. It’s difficult to deliver medicines of any sort to the brain. The genetics of these diseases are often more complex, involving multiple genes or mutations that vary in length. There have been many important advances in this area in the past few years, and we’re very hopeful that we can make progress on neurodegenerative diseases in the coming years because it’s an area that is very much in need of new treatment options.

    Bruno, why investigate sickle cell anemia, how can gene editing help and what are the main challenges?

    Sickle cell anemia is a serious health issue in Brazil, especially in the state of Bahia, where the occurrence rate is high, affecting 1 in every 650 live births. For many years, this condition was neglected and little investment has been made in new treatments. Recently, gene therapy has opened new treatment perspectives.

    Using gene therapy with the CRISPR technique, it is possible to correct the genetic defect responsible for sickle cell anemia. The process involves collecting stem cells from the patient, gene editing them in a laboratory, and then transplanting the corrected cells back into the patient.

    However, it is important to highlight that these therapies can cost up to US$2 million per patient, which limits access to them. Our goal is to develop more accessible treatment alternatives that significantly reduce the costs involved. We are committed to making sickle cell anemia treatment more accessible for everyone, thus contributing to improving the quality of life of those who suffer from this condition in Brazil.

    What approach did you choose to treat sickle cell anemia and why?

    Sickle cell anemia is a genetic condition caused by a specific point mutation in the hemoglobin gene, which is the protein responsible for transporting oxygen within red blood cells. This mutation results in a dysfunction in hemoglobin, compromising its function and generating symptoms of the disease, such as intense pain and risks of vascular complications. One promising alternative we are exploring involves turning off the gene with the mutation responsible for sickle cell anemia and turning on the gene that codes for a different form of hemoglobin, produced during embryonic development. The CRISPR method has been used to increase the amount of this fetal hemoglobin in patients’ cells. Studies conducted in the United States and China have demonstrated the effectiveness of this procedure in controlling the symptoms of the disease.

    One innovation we are researching to make these therapies more accessible involves modifications to the way we deliver CRISPR to a patient’s cells. Improving this process could result in significant cost reduction for these therapies, making them accessible to a greater number of people.

    Dr. Doudna, are you concerned with the fair access to CRISPR treatments once they become a reality?

    I’m very concerned about fair access. The first generation of CRISPR therapies are going to be very expensive and only available in certain places. This is a common pattern in any new technology, but when you have a potentially life-saving therapy, it’s hard to ask people to just wait for the price to go down. The solution to this problem is both on the technological side and the regulatory side.

    How do we develop therapies that can be manufactured more cheaply and administered everywhere? How do regulators create incentives to develop affordable cures for common and rare diseases when it doesn’t fit the standard business model of the pharmaceutical industry? Challenging questions, but ones we need to work on now and not just hope that it all works out.

    Bruno, the UK (MHRA) and American (FDA) health regulatory agencies approved at the end of 2023 the first gene therapy to cure sickle cell anemia. This is a technique very similar to the one you are researching at IGI. How is this technique different from yours and how important is this milestone for this and other gene editing research?

    Although there are similarities between the Vertex/CRISPR therapeutics company’s technique and that of IGI — for example, gene editing occurs in an ex vivo context, that is, cells are collected and edited in the laboratory, followed by transplantation to the patient — there are also differences in the way the process is being carried out in our project, as we seek simplifications that can contribute to cost reduction and greater dissemination of the technology.

    The fact that this therapy was approved for commercial use just 10 years after the discovery of CRISPR/Cas9 is a milestone and a great achievement, as it is the first CRISPR therapy available on the market. I believe this is just the beginning of a revolution that we hope will benefit many patients.

    Thyago, we have been seeing remarkable advances in the diagnosis and understanding of Alzheimer’s Disease in recent years/months. But as Dr. Doudna said above, developing treatments for neurodegenerative diseases like this is more complicated, even using CRISPR. How has your experience been at IGI and what are the strategies for advancing this research?

    My experience has been excellent precisely because we are constantly thinking outside the box, about new ways of applying (epi)genetic editing with CRISPR-Cas to complex and multifactorial diseases, such as Alzheimer’s disease.

    We know that, although the technique was initially developed for gene editing applications, today we have a variety of “flavors” of CRISPR-Cas that can be applied to different problems, such as sporadic Alzheimer’s disease, mental disorders, diabetes, cardiovascular disease and others.

    We also know that one of the biggest challenges with gene therapies, whether with CRISPR-Cas or not, comes from the difficulty of delivering editing systems to target tissues in a specific, efficient way and without prohibitive side effects. This is also actively studied, with teams dedicated to this effort at IGI, and which we are also interested in contributing to. Fortunately, from a regulatory perspective, given the modularity of CRISPR-Cas tools, once one therapy advances, the others will have an easier time being adopted clinically for other purposes.

    How can recent advances in Alzheimer’s research help direct CRISPR research? Is it possible, for example, to create genetically altered mini-brains using CRISPR to investigate in vitro the cause-effect relationship of tau and beta-amyloid proteins in disease progression?

    As research into biomarkers and early diagnosis for Alzheimer’s disease advances, the better is the window for intervention using advanced (or prophylactic) CRISPR-based therapies for epigenetic editing. The example you mention is a clear application of the technique for developing genetically altered organoid models, which can be used – among other things – to help determine cause-effect relationships of the aforementioned proteins. Furthermore, the technique also accelerates the creation of cells and animal models with specific genotype and phenotype.

    Dr. Doudna, you support an ethical framework that calls for an embargo on gene editing for human embryos. Are you specifically concerned with the safety of the current technology to do so? Or do you believe there’s something fundamentally unethical about altering human genes, even if it could be done safely?

    The safety of editing human germline cells is of paramount importance, and the technology is not currently in a place where we can do this with the safety and precision required. The ethical question is one that might change over time. There may come a time when it would be seen as unethical not to treat when we have the ability to do so, but first we would have to be able to edit germline cells safely and precisely, and we would have to find a scenario where there is no better alternative. It’s important to stress that the vast majority of genetic diseases can be treated using somatic cell editing, which just affects a single individual and is not heritable. This is where the field is focused at the moment and where we will be seeing the biggest advances.

    Bruno, Thyago, what other CRISPR applications in medicine do you consider most promising and why? Does the IGI research group also evaluate the possibility of using the technique to, for example, combat viruses (as bacteria do)?

    Bruno: Improving CRISPR delivery methods is crucial to expanding the range of possible treatments.

    Up until now, CRISPR has mainly been used to edit cells that can be taken from the body, modified in the laboratory and then reintroduced into the patient. However, our ultimate goal is to develop highly effective and selective delivery methods that allow gene editing directly in the organism, in vivo.

    Another point of great relevance is that CRISPR was initially applied to the treatment of diseases caused by a single gene or specific cancers. The current trend is that this technology can be increasingly used in the future to treat complex diseases, such as cardiovascular and neurological diseases, for example. This means we can potentially address a wider range of health conditions, offering new hope and more effective treatments to more people.

    Thyago: Without going into details of other colleagues’ projects, yes, there is interest in the use of epigenetic editing, for example, to regulate the immune response to different pathogens. Not only for treatment, but there are already efforts to make immune system cells more “combative” and “effective” even before exposure or infection.

    Personally, in addition to what we said about the potential for intervention in genetic diseases, I believe in the application of epigenetic editing to help in the treatment of mental disorders, chemical dependency, and other complex diseases that require advanced interventions, given the ineffectiveness of traditional pharmacological therapies.

    These studies are already underway and can help solve social and public health problems that have limited and, at times, ineffective options. Of course, highlighting that these advances can happen not only in treatment, but in the use of CRISPR in basic research to better understand the etiology.

    Bruno, Thyago, what is your opinion on the partnership between Pioneer Science, IDOR and IGI? Honestly, how can a partnership like this help develop science in the world, what difference does the participation of Brazilian scientists/institutions make (globally and for the country) and what importance does this have for researchers like you? Does this type of partnership have the potential to truly contribute to the advancement of maverick science and attract more interest from Brazilian minds?

    The partnership between Pioneer Science, IDOR and IGI is a unique opportunity to boost science in Brazil and integrate scientists into projects of global relevance. This collaboration not only benefits research, but can also have a lasting positive impact, helping to reverse the brain drain and attracting more talent to contribute to the advancement of knowledge and innovation in the country. Furthermore, I hope that initiatives like this partnership can contribute to catalyzing essential discussions about the need to review the current model for promoting science in Brazil, paving the way for a more innovative future in our scientific community.

    The partnership is essential not only for our technical training, but for the establishment of international academic collaborations that will help advance frontier science. Each nation has a repertoire of social and health problems that are generally not of global interest, highlighting the importance of having researchers trained with state-of-the-art tools committed to advancing on these problems. Furthermore, these great partnerships serve to inspire new scientists, both their careers and their interest in carrying out cutting-edge research outside the predominant model of Universities.

    Dr. Doudna, how do you see the potential of IGI-IDOR Pioneer Science collaboration in basic science and in clinical trials in Brazil to help improve access of patients in developing countries to CRISPR-based therapies in the future?

    My lab and my colleagues at Innovative Genomics Institute are doing a lot of work in the CRISPR space, but we can’t be everywhere all at once, and we won’t have the same priorities as an institute in a different part of the world. It’s important for us to help build local capacity with collaborations like we have with IDOR / Pioneer Science in Brazil, and it’s essential that we work to improve access wherever these new therapies can be of most help, not just in the US market.

    Bruno, Thyago, how was the researchers’ meeting in Rio de Janeiro and how important could it be for the partnership and the development of research?

    Bruno: The meeting was very important for several reasons. From a strategic perspective, it was important to review the progress of the program and define priorities for the next steps. Also, the IGI team had the opportunity to learn about the local infrastructure and capabilities for the continuity of the projects.

    Thyago: The meeting was very fruitful, especially because, in addition to the more technical sessions, we also discussed the future of new partnerships, scientific dissemination, new fellows and new projects of the IGI-PC collaboration. Pioneer Science is a novel initiative, and events like this one are essential to align the long-term objectives and mission, in addition to publicizing the program to Brazilian scientists who would like distinctive training and aimed at scientific development in our country.

    Bruno, Thyago, the IDOR laboratories in the cities of Salvador and São Paulo will also participate in these studies, right? What will this participation be like?

    Bruno: In Salvador, we have a unique infrastructure focused on advanced therapies. We have an internationally certified cell therapy laboratory (JACIE) and have accumulated knowledge through our participation in several pre-clinical and clinical studies in this area. One of the main focuses of this collaboration with IGI is the study of sickle cell anemia, a highly prevalent condition in Bahia. In this context, technology transfer is extremely important so that we can expand and multiply these studies in Salvador.

    Thyago: Yes, Pioneer Science is initially in three cities: Rio de Janeiro, Salvador and São Paulo. The researchers involved with the program will be divided according to the existing structure, area of activity and logistics. In addition to the internationally certified cell therapy space in Salvador, we also have laboratories being specifically designed to meet the program’s mission and continuity of established projects and partnerships, whether of basic research, translational, or clinical studies. In addition to Brazilian scientists, the Pioneer Science laboratories can also temporarily receive colleagues from international partner institutions to strengthen collaborations and help with technical implementation.

    Pioneer Science has also signed agreements with other universities and research centers. Among them are Weizmann Institute of Science (Israel), Quantum Biology Tech Lab at UCLA (USA), Usona Institute (USA), Stanford University (USA), King’s College London (England), Federal University of Rio de Janeiro (Brazil) and Federal University of Minas Gerais (Brazil).

    See also the infographic “How to treat sickle cell anemia using CRISPR gene editing”.


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