Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI)

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative.

Recent Progress of Machine Learning in Gene Therapy

: With new developments in biomedical technology, it is now a viable therapeutic treatment to alter genes with techniques like CRISPR. At the same time, it is increasingly cheaper to do whole genome sequencing, resulting in rapid advancement in gene therapy and editing in precision medicine. Thus, understanding the current industry and academic applications of gene therapy provides an important backdrop to future scientific developments. Additionally, machine learning and artificial intelligence techniques allow for the reduction of time and money spent in the development of new gene therapy products and techniques. In this paper, we survey the current progress of gene therapy treatments for several diseases and explore machine learning applications in gene therapy. We also discuss the ethical implications of gene therapy and the use of machine learning in precision medicine. Machine learning and gene therapy are both topics gaining popularity in various publications, and we conclude that there is still room for continued research and application of machine learning techniques in the gene therapy field.

How art-as-therapy supports participants with a diagnosis of schizophrenia : a phenomenological investigation

Although art therapy is recommended in management programmes for individuals with a diagnosis of schizophrenia, calls have been made for more detailed explanations as to how artmaking is working. This study responds to those calls by considering the artmaking experiences of 15 mental health users with a diagnosis of schizophrenia, resident at a forensic, mental health facility in South Africa. A phenomenological approach was chosen because of its focus on lived experiences, suited to explore the embodied and pre-reflective experience of studio-based artmaking. Dialogical and narrative understandings were subsequently incorporated to account for more reflective aspects of the artmaking experience. Two main participant descriptions of artmaking, centring on feeling at home and on doing something meaningful, guided the phenomenological lifeworld method in analysing the data (interviews, artworks and field observations in art groups and exhibitions), along selected dimensions of lived experience, namely embodiment, temporality, spatiality, sociality and selfhood. These findings lend support to new phenomenological research which suggests that artmaking intersects with disrupted abilities for perceptual engagement underlying manifestations of schizophrenia symptomology. This research supports assertions that artmaking has the potential to support the minimal sense of self and expand possibilities for renewed embodied and more reflective meaning-making. Explanations of findings centred around the distinct artistic style of each participant, as well as their artworks which revealed individual lifeworlds including a variety of self-positions. The inherent properties of the completed artworks also provided possibilities for renewed experiences of sociality. Additional support for the findings is drawn from recent research in the fields of early neurodevelopmental trauma, and trauma research findings within the art therapy field.

Gene Therapy for Inherited Bleeding Disorders

Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to regulatory approval. However, this recent success should not obscure the multiple challenges that were overcome to reach this destination. Gene therapy for hemophilia A and B benefited from advancements in the general gene therapy field, such as the development of adeno-associated viral vectors, as well as disease-specific breakthroughs, like the identification of B-domain deleted factor VIII and hyperactive factor IX Padua. The gene therapy field has also benefited from hemophilia B clinical studies, which revealed for the first time critical safety concerns related to immune responses to the vector capsid not anticipated in preclinical models. Preclinical studies have also investigated gene transfer approaches for other rare inherited bleeding disorders, including factor VII deficiency, von Willebrand disease, and Glanzmann thrombasthenia. Here we review the successful gene therapy journey for hemophilia and pose some unanswered questions. We then discuss the current state of gene therapy for these other rare inherited bleeding disorders and how the lessons of hemophilia gene therapy may guide clinical development.

Viral vector platforms within the gene therapy landscape

Throughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to patients and families with limited treatment options, but has also been subject to many setbacks. Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and, even in rare cases, death. At the heart of this dichotomous field are the viral-based vectors, the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms, and have radically changed the face of medicine. Within the past 5 years, the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes. These modalities range from vector-based cancer therapies, to treating monogenic diseases with life-altering outcomes. At present, the three key vector strategies are based on adenoviruses, adeno-associated viruses, and lentiviruses. They have led the way in preclinical and clinical successes in the past two decades. However, despite these successes, many challenges still limit these approaches from attaining their full potential. To review the viral vector-based gene therapy landscape, we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.

Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors

Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and impaired T-cell quality due to the presence of an immunosuppressive tumor microenvironment, which affect the safety and limit efficacy of CD3-bispecific antibody therapy. In this review, we provide a brief status update of the CD3-bispecific antibody therapy field and identify intrinsic hurdles in solid cancers. Furthermore, we describe potential combinatorial approaches to overcome these challenges in order to generate selective and more effective responses.

Development and Evaluation of Monoxide Based Flexible Skin Dosimeter for Radiotherapy at Photon Energies

Radiation therapy uses high-energy radiation that can cause various side effects depending on the patient's exposure. In particular, side effects occur in the skin due to its radiation exposure to reach the target volume. Therefore, side effects are reduced by clinical trials using various skin dosimeters such as films and glass detectors to determine the dose exposed to the skin. However, accurately measuring the doses using these dosimeters is challenging due to human curvature. In this study, a flexible skin dosimeter was produced using the photoconductor materials mercury oxide (HgO) and lead oxide (PbO). The performance of the proposed dosimeter was evaluated by measuring reproducibility, linearity, dose rate independency according to dose, and percent depth dose (PDD) at photon energy beam. The results showed that the flexible skin dosimeter using HgO material has high applicability as a skin dosimeter due to its stability compared to PbO. The results provide useful insights for the radiation therapy field, particularly in areas where radiation measurement is difficult, depending on the human curvature. The proposed flexible skin dosimeter could serve in various radiation detection areas as a flexible, functional material