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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.

We and others have recently shown that p16 can potently and specifically inhibit progression through the G1 phase of the replicative cycle in cells that express the retinoblastoma protein (pRB). However, none of these studies examined cell types in which p16 has been firmly implicated in tumorigenesis. We predicted that such cells would show sensitivity to p16 inhibition, perhaps conferred by proteins in addition to or other than pRB. Intragenic, inactivating mutations of p16 have been found at significant frequency in primary tumors derived from squamous epithelial cells of the esophagus (ESCC). We therefore examined p16 function in ESCC lines and in primary squamous epithelial cells cultured from mouse skin. We find that seven of eight ESCC lines tested are inhibited by p16 and fail to express the protein endogenously. The lone p16-resistant line expresses endogenous p16 but lacks functional pRB. Primary squamous epithelial cells are also inhibited by p16. These data suggest that squamous epithelial cells are generally sensitive to inhibition by a regulatory pathway that involves p16 and pRB, and that, by the time of establishment in culture, there is nearly universal inactivation of this pathway in ESCCs.

The retinoblastoma gene product, pRB, regulates cell proliferation by binding to and inhibiting the activity of key growth promoting proteins. Several cellular proteins have been shown to bind directly to pRB and the genes encoding a number of them have been isolated. The protein product of one of these genes is the transcription factor E2F. We have now isolated cDNA clones that contain the full-length coding sequence of two other proteins, RBP1 and RBP2, cloned originally by their interaction with pRB. The products of the RBP1 and RBP2 genes are ubiquitously expressed, large (200 kDa for RBP1 and 195 kDa for RBP2) nuclear phosphoproteins with structural motifs that suggest a role in transcriptional regulation. In addition we have been able to identify complexes of pRB and RBP1 in vivo that are dissociated in the presence of purified human papillomavirus E7 protein.

NUMEROUS STUDIES have been made on the respiration of land plants and some on water plants, but very few such studies have been made on semi-submerged water plants (Samantarai, 1938). Yet, from the standpoint of the environment, semi-submerged plants offer very interesting material because of the belief that they were once terrestrial and have subsequently invaded the water, and because it is difficult to understand how the rhizomes of plants with terrestrial form are able to endure the condition of low aeration that exists in the mud at the bottom of a pond (Cole, 1932).2 That this ability is not due to particular structural features may be deduced from the fact that rhizomes of very diverse structures are found imbedded in the submerged mud. For example, Furthermore, the ability to endure the nearly anaerobic conditions of the submerged mud is not associated with a particular habit of growth and fruiting, because all of the species of thick spongy rhizomes mentioned above as well as one of the toughest and firmest of rhizomes to be found anywhere, namely, that of Scirpus validus, grow progressively through the mud, branching only occasionally, sending up fruiting culms at irregular intervals, and always dying and becoming decayed at the rear; while the hard young rhizomes of Typha latifolia and Sparganiurn eurycarpum and the corms of Sagittaria latifolia are formed one at the terminal end of each of the slender spongy stolons that radiate from a parent plant which dies at the end of its fruiting season.

1. Semi-submerged water plants inhabit their particular habitats very largely on the basis of adaptation in respect to their oxygen requirements for respiration and growth. The oxygen requirements for growth are different for different species. 2. The percentage of oxygen found to be most conducive to the growth of young shoots in certain of the species studied was, respectively, Nuphar advenum 0 to 1, Peltandra virginica 0 to 1.5, Pontederia cordata 0 to 10, Typha latifolia 4.6, Acorus calamus 10, Scirpus validus 10. Buds of all these species were able to endure prolonged exposure to pure nitrogen, but no growth occurred in A. calamus, S. validus, and T. latifolia in nitrogen. Shoots of S. validus previously formed were killed in nitrogen. 3. The excellent growth of N. advenum in nitrogen was not affected by either the presence or absence of oxygen in the internal atmosphere of the rhizome so long as the apex was surrounded by nitrogen. When the apex was surrounded by air, no growth occurred even though ...