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Abstract Patient involvement is crucial in healthcare, a factor increasingly recognised by life sciences companies and research institutes. This article presents a case study on Servier, a life sciences company that founded a patient expert board, ahead of launching a new research and development (R&D) institute. The aim was to foster a patient-centric culture within the company. The case study explores key developments in patient and public involvement, emphasising a shift from paternalistic to patient-centred approaches, noting few available case studies on patient board collaborations in life sciences. It outlines the evolution of the board, its impact, and practical lessons learned, with related recommendations. The patient board resulted from a three-way collaboration between the company, Patvocates (a patient consultancy), and patient experts recruited. The patient consultancy played a crucial role in project management, governance, and facilitating relationships. The case study provides the context, timeframe, foundations laid, engagement of patient experts, and foundational values, including: co-creation, fair market value remuneration, voluntary participation, and patient-centric meeting protocol. Eighteen patient experts, representing ten disease areas and ten European countries, joined the board and helped prioritise and co-create projects. Ideas for activities were sourced from brainstorming sessions and an in-company challenge. The collaboration yielded five core ideas, each forming a working group. The study describes the groups and their outputs: a patient advisory council, an interactive gallery of patient experience in R&D, patient engagement and entrepreneurship in life sciences, creating patient-focused decentralised trials (DCTs), and staff training on patient engagement. The article emphasises how the organic evolution of the collaboration led to significant insights. Hurdles faced by the company included: upstream planning, cross-company buy-in, compliance, and internal resource allocation. Recommendations for the wider community included: identifying and contracting patient partners; clarifying roles; managing expectations; building trust; logistics; and sustainability. This case study presents a practical, positive example of patient engagement within a life sciences company, offering insights into the establishing, running, and the impact of collaborating with a patient expert board. Lessons learned and recommendations may serve as a model for other companies seeking to engage with patients and evolve towards a more patient-centric approach in their strategies.

Presently, human collagen VI-related diseases such as Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) remain incurable, emphasizing the need to unravel their etiology and improve their treatments. In UCMD, symptom onset occurs early, and both diseases aggravate with ageing. In zebrafish fry, morpholinos reproduced early UCMD and BM symptoms but did not allow to study the late phenotype. Here, we produced the first zebrafish line with the human mutation frequently found in collagen VI-related disorders such as UCMD and BM. We used a transcription activator-like effector nuclease (TALEN) to design the col6a1ama605003-line with a mutation within an essential splice donor site, in intron 14 of the col6a1 gene, which provoke an in-frame skipping of exon 14 in the processed mRNA. This mutation at a splice donor site is the first example of a template-independent modification of splicing induced in zebrafish using a targetable nuclease. This technique is readily expandable to other organisms and can be instrumental in other disease studies. Histological and ultrastructural analyzes of homozygous and heterozygous mutant fry and 3 months post-fertilization (mpf) fish revealed co-dominantly inherited abnormal myofibers with disorganized myofibrils, enlarged sarcoplasmic reticulum, altered mitochondria and misaligned sarcomeres. Locomotion analyzes showed hypoxia-response behavior in 9 mpf col6a1 mutant unseen in 3 mpf fish. These symptoms worsened with ageing as described in patients with collagen VI deficiency. Thus, the col6a1ama605003-line is the first adult zebrafish model of collagen VI-related diseases; it will be instrumental both for basic research and drug discovery assays focusing on this type of disorders.

Meganucleases are sequence-specific endonucleases recognizing large (>14 bp) sequences. Because of this unusual specificity, meganuclease have emerged as powerful tools for genome engineering: creation of double-strand breaks by meganucleases at specific loci can be used to enhance homologous gene targeting by several orders of magnitude in mammalian and plant cells. Recently, such proteins could be used to induce gene repair in mouse hepatocytes, paving the way for a novel strategy for inherited diseases therapy based on gene correction instead of complementation. Thus, the generation of meganucleases with tailored specificities is under intense investigation. A major issue is whether it is possible to obtain novel dedicated endonuclease which levels of specificity compatible with the high requirements of therapeutic applications.Homing endonucleases (HEs) are natural meganucleases encoded by mobile genetic elements such as class I introns and inteins. Their exquisite specificity identifies them as ideal scaffolds to derive novel meganucleases with engineered DNA binding domains. HEs from the LAGLIDADG family, the largest and most widespread family of HEs, display two independent domains or units. Moreover, despite the lack of apparent additional modularity at the structural level, we have identified separable functional subdomains within a same LAGLIDADG domain binding distinct parts of the DNA target. Using a semi-rational approach, we have used a two steps strategy to produce meganucleases cleaving natural genes. In a first step, we have derived hundreds of novel meganucleases with novel specificities from I-CreI, a natural homodimeric homing endonuclease. In a second step, a combinatorial approach allows us to assemble these I-CreI variants into novel meganucleases with predictable cleavage site. Importantly, these proteins have retained high levels of specificity. Examples of meganucleases with potential therapeutic applications will be disclosed.Molecular Therapy (2006) 13, S366–S366; doi: 10.1016/j.ymthe.2006.08.1040 [ABSTRACT FROM AUTHOR]