Social pharmaceutical innovation and alternative forms of research, development and deployment for drugs for rare diseases

Rare diseases are associated with difficulties in addressing unmet medical needs, lack of access to treatment, high prices, evidentiary mismatch, equity, etc. While challenges facing the development of drugs for rare diseases are experienced differently globally (i.e., higher vs. lower and middle income countries), many are also expressed transnationally, which suggests systemic issues. Pharmaceutical innovation is highly regulated and institutionalized, leading to firmly established innovation pathways. While deviating from these innovation pathways is difficult, we take the position that doing so is of critical importance. The reason is that the current model of pharmaceutical innovation alone will not deliver the quantity of products needed to address the unmet needs faced by rare disease patients, nor at a price point that is sustainable for healthcare systems. In light of the problems in rare diseases, we hold that re-thinking innovation is crucial and more room should be provided for alternative innovation pathways. We already observe a significant number and variety of new types of initiatives in the rare diseases field that propose or use alternative pharmaceutical innovation pathways which have in common that they involve a diverse set of societal stakeholders, explicitly address a higher societal goal, or both. Our position is that principles of social innovation can be drawn on in the framing and articulation of such alternative pathways, which we term here social pharmaceutical innovation (SPIN), and that it should be given more room for development. As an interdisciplinary research team in the social sciences, public health and law, the cases of SPIN we investigate are spread transnationally, and include higher income as well as middle income countries. We do this to develop a better understanding of the social pharmaceutical innovation field’s breadth and to advance changes ranging from the bedside to system levels. We seek collaborations with those working in such projects (e.g., patients and patient organisations, researchers in rare diseases, industry, and policy makers). We aim to add comparative and evaluative value to social pharmaceutical innovation, and we seek to ignite further interest in these initiatives, thereby actively contributing to them as a part of our work

In vivo zygotic- and maternal-effect characterization of the Drosophila melanogaster gene, tango.

This study involved the in vivo phenotypic characterization of the Drosophila melanogaster gene tango (tgo) through classification of both its zygotic-effect during CNS development and maternal-effect during early embryonic patterning. Particularly, this study involved characterization of the prd-repeat domain of the Tango protein, or its allelic equivalent, tgo 3. tgo has been previously isolated as a bHLH-PAS nuclear transcription factor required in the regulation of CNS development through its dimerization of the CNS master transcriptional regulatory gene, single-minded. Having performed an inter-allelic analysis, I grouped the CNS zygotic effects of tgo into various phenotypic classifications. The phenotypes exhibited a pleiotropy of CNS mutant effects and were classified as fused commissure, neurogenic, stalled or ambiguous nervous system defects. These phenotypes may possibly be attributed to different but partially overlapping functions of the various Tgo domains. Additionally, I analyzed the maternal-effect of tgo during precellular blastoderm development. Germline clonal analysis of the tgo3 allele revealed that tgo has an important role during early embryogenesis. Moreover, maternal tgo3 phenotypes resemble those of the more well-characterized maternal coordinate and gap segmentation genes. tgo3 germline clones were embryonic lethal and were classified as severe or intermediate, depending on the extent of deleterious effects on the resultant cuticular phenotype. Germline clones that showed a deletion of the entire anterior end, abdominal segments Al to A5 and missing the Filzkorper and spiracular opening in the posterior end were classified as severe and are comparable to the cuticular phenotypes of amorphic bicoid mutants and Kruppel ( Kr) phenotypes. Less severe deleterious effects, such as improper development of various anterior and posterior end structures or aberrant denticle band formation, were classified as intermediate tgo 3 germline clones, comparable to weaker bicoid alleles. Subsequent stainings to observe the effect on embryonic patterning through gap and pair-rule protein localization revealed alterations in spatial expression patterns. Alterations in both Kruppel and Even-skipped localization patterns in embryos mutant for maternal tgo3 suggest a role for tgo during early embryonic patterning, perhaps through the activity of its prd-repeat domain. Ectopic expression studies, employing the GAL4-UAS system, involved heat shock trials eliciting the ubiquitous expression of a truncated C-terminal Tgo protein (UAS-tgoDeltaC ) and both the ubiquitous land targeted expression of UAS- tgoDeltac. This targeted misexpression analysis revealed tgo as both a possible activator and repressor of Kr gap gene expression, in addition to affecting the protein distribution pattern of the later-acting segmentation gene, engrailed. Taken together, these germline clonal and ectopic expression studies suggest that the role of Tgo during early embryonic patterning may function through combinatorial interactions with maternal-effect and/or early-acting segmentation gene products. Moreover, this role may depend on the function(s) of the C-terminal sequences encoded by Tgo, including the prd repeat domain. Ultimately, this early embryonic role of tgo seems to be distinct from its role as a nuclear transcription factor

Social pharmaceutical innovation and alternative forms of research, development and deployment for drugs for rare diseases

Rare diseases are associated with difficulties in addressing unmet medical needs, lack of access to treatment, high prices, evidentiary mismatch, equity, etc. While challenges facing the development of drugs for rare diseases are experienced differently globally (i.e., higher vs. lower and middle income countries), many are also expressed transnationally, which suggests systemic issues. Pharmaceutical innovation is highly regulated and institutionalized, leading to firmly established innovation pathways. While deviating from these innovation pathways is difficult, we take the position that doing so is of critical importance. The reason is that the current model of pharmaceutical innovation alone will not deliver the quantity of products needed to address the unmet needs faced by rare disease patients, nor at a price point that is sustainable for healthcare systems. In light of the problems in rare diseases, we hold that re-thinking innovation is crucial and more room should be provided for alternative innovation pathways. We already observe a significant number and variety of new types of initiatives in the rare diseases field that propose or use alternative pharmaceutical innovation pathways which have in common that they involve a diverse set of societal stakeholders, explicitly address a higher societal goal, or both. Our position is that principles of social innovation can be drawn on in the framing and articulation of such alternative pathways, which we term here social pharmaceutical innovation (SPIN), and that it should be given more room for development. As an interdisciplinary research team in the social sciences, public health and law, the cases of SPIN we investigate are spread transnationally, and include higher income as well as middle income countries. We do this to develop a better understanding of the social pharmaceutical innovation field’s breadth and to advance changes ranging from the bedside to system levels. We seek collaborations with those working in such projects (e.g., patients and patient organisations, researchers in rare diseases, industry, and policy makers). We aim to add comparative and evaluative value to social pharmaceutical innovation, and we seek to ignite further interest in these initiatives, thereby actively contributing to them as a part of our work.Pharmaceutical Sciences, Faculty ofNon UBCReviewedFacultyResearche