Telethon Foundation

ABSTRACT BACKGROUND: Wiskott-Aldrich Syndrome (WAS) is a rare, X-linked, life-threatening inborn error of immunity and platelet disorder caused by WAS protein (WASP)-encoding gene mutations. Etuvetidigene autotemcel (etu-cel) is an autologous gene therapy (GT) consisting of hematopoietic stem progenitor cell (HSPCs) transduced ex vivo with a lentiviral vector encoding human WAS cDNA. METHODS Etu-cel was intravenously infused after rituximab and reduced-intensity conditioning. Data from WAS patients treated in two prospective open-label clinical trials (phase I/II n=8; phase III n=10) and one expanded access program (EAP) (n=9) were integrated to evaluate efficacy and safety of etu-cel. Primary efficacy endpoints were overall survival, rate of severe infections from 6 to 18 months after GT and rate of moderate/severe bleeding episodes in the first 12 months post-treatment compared with 1 year prior to GT. Secondary efficacy endpoints included engraftment of gene-corrected cells, WASP expression, T-cell function, platelet count, autoimmunity and eczema over time. Safety endpoints included adverse events (AEs), immune response to transgene, development of replication-competent lentivirus (RCL) and abnormal clonal proliferation (ACP). RESULTS Median follow-up was 5.7 years (range: 0.4-13.3). Median age at treatment was 2.6 years (range: 1.0-35.1). Overall survival was 96%; one EAP subject died early post-GT due to deterioration of a pre-existing neurological condition. The rate of severe infections per person-year of observation (PYO) decreased from 2.00 (95% CI: 1.50-2.61) pre-GT to 0.15 (95% CI: 0.04-0.39) in the 6-18 months period post-GT. The rate of moderate and severe bleeding events per PYO decreased from 2.00 (95% CI: 1.50-2.61) to 0.80 (95% CI: 0.49-1.22) in the 12 months after GT. After GT, multilineage engraftment of gene-corrected cells was sustained over time. WASP expression in platelets and lymphocytes increased. Platelet count, T-cell functionality, eczema and autoimmunity improved. The most common adverse event ≥ grade 3 was device related infection. Etu-cel was well-tolerated with no treatment-related adverse events and no evidence of insertional oncogenesis. CONCLUSIONS With up to 13 years follow-up, etu-cel demonstrates a favorable benefit-risk profile, leading to sustained long-term clinical benefit. (Funded by GlaxoSmithKline [GSK], Orchard Therapeutics, Fondazione Telethon; ClinicalTrials.gov numbers: NCT01515462 , NCT03837483 )

Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind.

Charities investing on rare disease research greatly contribute to generate ground-breaking knowledge with the clear goal of finding a cure for their condition of interest. Although the amount of their investments may be relatively small compared to major funders, the advocacy groups' clear mission promotes innovative research and aggregates highly motivated and mission-oriented scientists. Here, we illustrate the case of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), the main Italian funding agency entirely dedicated to amyotrophic lateral sclerosis research. An international benchmark analysis of publications derived from AriSLA-funded projects indicated that their mean relative citation ratio values (iCite dashboard, National Institutes of Health, U.S.) were very high, suggesting a strong influence on the referring international scientific community. An interesting trend of research toward translation based on the "triangle of biomedicine" and paper citations (iCite) was also observed. Qualitative analysis on researchers' accomplishments was convergent with the bibliometric data, indicating a high level of performance of several working groups, lines of research that speak of progression toward clinical translation, and one study that has progressed from the investigation of cellular mechanisms to a Phase 2 international clinical trial. The key elements of the success of the AriSLA investment lie in: (i) the clear definition of the objectives (research with potential impact on patients, no matter how far), (ii) a rigorous peer-review process entrusted to an international panel of experts, (iii) diversification of the portfolio with ad hoc selection criteria, which also contributed to bringing new experts and younger scientists to the field, and (iv) a close interaction of AriSLA stakeholders with scientists, who developed a strong sense of belonging. Periodic review of the portfolio of investments is a vital practice for funding agencies. Sharing information between funding agencies about their own policies and research assessment methods and outcomes help guide the international debate on funding strategies and research directions to be undertaken, particularly in the field of rare diseases, where synergy is a relevant enabling factor.

BackgroundEar and hearing care programs are critical to early detection and management of otitis media (or middle ear disease). Otitis media and associated hearing loss disproportionately impacts First Nations children. This affects speech and language development, social and cognitive development and, in turn, education and life outcomes. This scoping review aimed to better understand how ear and hearing care programs for First Nations children in high-income colonial-settler countries aimed to reduce the burden of otitis media and increase equitable access to care. Specifically, the review aimed to chart program strategies, map the focus of each program against 4 parts of a care pathway (prevention, detection, diagnosis/management, rehabilitation), and to identify the factors that indicated the longer-term sustainability and success of programs.MethodA database search was conducted in March 2021 using Medline, Embase, Global Health, APA PsycInfo, CINAHL, Web of Science Core Collection, Scopus, and Academic Search Premier. Programs were eligible or inclusion if they had either been developed or run at any time between January 2010 to March 2021. Search terms encompassed terms such as First Nations children, ear and hearing care, and health programs, initiatives, campaigns, and services.ResultsTwenty-seven articles met the criteria to be included in the review and described a total of twenty-one ear and hearing care programs. Programs employed strategies to: (i) connect patients to specialist services, (ii) improve cultural safety of services, and (iii) increase access to ear and hearing care services. However, program evaluation measures were limited to outputs or the evaluation of service-level outcome, rather than patient-based outcomes. Factors which contributed to program sustainability included funding and community involvement although these were limited in many cases.ConclusionThe result of this study highlighted that programs primarily operate at two points along the care pathway—detection and diagnosis/management, presumably where the greatest need lies. Targeted strategies were used to address these, some which were limited in their approach. The success of many programs are evaluated as outputs, and many programs rely on funding sources which can potentially limit longer-term sustainability. Finally, the involvement of First Nations people and communities typically only occurred during implementation rather than across the development of the program. Future programs should be embedded within a connected system of care and tied to existing policies and funding streams to ensure long term viability. Programs should be governed and evaluated by First Nations communities to further ensure programs are sustainable and are designed to meet community needs.

The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases. IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies. The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews. The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues. The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.

In 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research.