11/23/2023 0 Comments Capacity crunch meaningOne of the most intriguing findings in cognitive psychology is that the capacity of WM is in fact very limited, although there is some debate as to exactly how many items can be maintained and manipulated. Working memory (WM) is a system that allows us to store and manipulate small amounts of information for a short time ( Baddeley, 1986 Baddeley & Hitch, 1974). Results are discussed in terms of Cowan’s model of working memory and theories of impaired inhibitory processes in aging. Interestingly, the brain activation data show a sigmoid relationship with load. The results suggest that age differences in brain activation can be largely attributed to individual variations in working memory span. Specifically, we hypothesized a nonlinear relationship between load and both performance and brain activity and predicted that asymptotes in the brain activation function should correlate with performance asymptotes (corresponding to working memory span). In a Sternberg memory search task, this can be achieved by assessing brain activity as a function of load relative to the individual’s memory span, which declines with age. The Compensation-Related Utilization of Neural Circuits Hypothesis leads to the prediction that activation differences between younger and older adults should disappear when task difficulty is made subjectively comparable. A possible interpretation of this finding is that older adults need to recruit neuronal resources at lower loads than younger adults, leaving no resources for higher loads, and thus leading to performance decrements. To avert a greater problem five years from now, when there will be dozens of commercial products on the market, the industry will need to add much more capacity, either externally or internally.Neuroimaging data emphasize that older adults often show greater extent of brain activation than younger adults for similar objective levels of difficulty. The shortage of capacity and long lead times with CDMOs have resulted in some biopharmaceutical companies slowing R&D and even delaying entry into the field. But currently there is a sizable gap between the development and manufacturing capabilities. Manufacturing capability is critical throughout the cell and gene therapy development process, from late-stage clinical trials to market. Together with Legend Biotech and Johnson & Johnson they lead the pack in terms of footprints and investments. Besides Legend Biotech and Johnson & Johnson, Pfizer, Novartis, Bayer, Biogen, and Biomarin are spending large sums on manufacturing. While smaller firms, including Solid Biosciences and Sarepta Therapeutics, are outsourcing, larger companies are making substantial capital investments in cell and gene therapy manufacturing capability. And so, last year, they committed $500 million to investing in building a new manufacturing facility in New Jersey. As a result, the two companies forecast that they will require a substantial boost in manufacturing capacity. The companies’ newly approved CAR-T agent for multiple myeloma, Carvykti, may see robust indication expansion in the coming years, with potentially tens of thousands more patients being prescribed the product. The decision last year by Legend Biotech and Johnson & Johnson to expand manufacturing aptly illustrates how companies are responding to and anticipating capacity issues. Starting with bigger pharmaceutical players-but also including some mid-sized ones-more and more firms are investing in in-house manufacturing to be able to meet the demands in clinical development and in anticipation of possible commercialization. However, CDMOs’ businesses are often stretched thin, which can mean significant wait times for manufacturing slots. To meet the increasing demand for gene therapies, Catalent is “ramping up” additions to its Maryland facilities. Catalent also supports other candidates in Sarepta’s pipeline. To illustrate, Catalent has served as the main commercial manufacturing partner for Sarepta Therapeutics in its quest to get its gene therapy to treat Duchenne muscular dystrophy across the finish line. As a leading CDMO, Catalent, for instance, has formed multiple long-term partnerships with biopharmaceutical companies. Indeed, CDMOs have played a vital role in cell and gene therapy production. Of the next dozen or so therapies expected to launch in 20 the majority is of the AAV type, specifically in vivo gene therapies.Ĭompanies can outsource manufacturing to contract development and manufacturing organizations (CDMOs). The process of extracting and purifying AAV vectors is difficult, in part because AAVs are produced in live cells in cell cultures. The emerging critical mass of clinical- and real-world experience for the adeno-associated virus (AAV) vector gene therapy platform gives it perhaps a leg up on others, producing a safe and effective AAV-based treatment isn’t easy.
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