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Engaging the FDA from an early time point helped to paint a confident development roadmap as did the trailblazing work from an earlier program led by Dr. Timothy Yu at Boston Children's Hospital.2 Through this collaboration, a new way of advancing life-saving medicine is born-a furthering of the template first forged by Dr. Yu in an effort to define a path for families, academics and clinicians to treat even a single patient impacted by a genetic disease. Concepts from as the potential for 2D and 3D tissue modeling in lieu of an animal model to test efficacy to common delivery platforms in the case of AAV reducing the need for repetitive vector toxicology. A recent report by McKinsey cited that 45% of respondents (cell and gene therapy companies) expected delay's of 3-6 months on average for development programs.4 Diving into the details, delay's regarding site activation for clinical trials, patient recruitment for trials and follow up appointments of enrolled patients were top areas of delays with 55% of respondents citing these three areas as delayed. Lessons such as allowing virtual trials visits informed by diagnostic tests being done locally rather than having the patient go to a clinical trial site thereby limiting visits, trial burden and potential exposure (even in a post-COVID world).

We treated a 27-year-old patient with Duchenne’s muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing d Sa Cas9 (i.e., “dead” Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR–transactivator therapy. The dose of rAAV used was 1×10 14 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.) A 27-year-old man with Duchenne’s muscular dystrophy who was treated with a CRISPR-Cas9 transgene died from an innate immune response to the high dose of recombinant AAV used for delivery of the transgene.

Nutritional requirements for vitamin D during pregnancy have been inadequately described, and there are conflicting data on the impact of gestation on vitamin D status. In the present study, we conducted a longitudinal analysis of total and free (unbound) serum 25-hydroxyvitamin D (25(OH)D), vitamin D-binding protein (DBP) and albumin concentrations in a random sample of thirty women from the Screening for Pregnancy Endpoints Ireland pregnancy cohort study at 15, 20, 24, 28, 32, 36 and 40 weeks of gestation and at 2 months postpartum. Concentrations of serum 25(OH)D, DBP and albumin were determined, and free 25(OH)D was calculated from the concentrations of total 25(OH)D, DBP and albumin. Serum albumin concentration decreased during pregnancy (P< 0·001), with a nadir at 36 weeks (P< 0·005), during which the concentration was approximately 80 % of the postnatal concentration. Serum DBP concentration increased during pregnancy and at 28 weeks of gestation, which was almost double the postnatal level (P< 0·001). Total and free 25(OH)D concentrations decreased (both P< 0·005) as pregnancy progressed, and both were lowest at 36 weeks of gestation. At 15 weeks, 10 and 63 % of the women had serum 25(OH)D concentration < 30 and 50 nmol/l, respectively, which increased to 53 and 80 % at 36 weeks of gestation. The time course of decreasing concentrations of 25(OH)D during gestation among women recruited during May–July, who delivered between October and November, and among those recruited in August–September, who delivered between February and March, was similar. The lower percentage of free 25(OH)D during pregnancy is mainly due to increased DBP.

Most investors have 2 objectives in common - immediate return on their investment and maximum capital appreciation over the term of the investment. A sustained increase in operating income creates the capital appreciation of a property, which creates value. Identification and exploitation of value creation opportunities can further the accomplishment of prime ownership objectives. Although value creation may express itself in a variety of ways, it always begins with an idea-generation process that involves reviewing the needs of the tenants and the needs of the marketplace. After this process has been completed, the feasibility of the ideas must be put to the test. All the major aspects of the feasibility equation must be explored - the physical, the structural, the legal, and the marketable. An overlooked cost or an ignorance of market forces will cause an idea to fail and may call the investor's judgment into question. Once the idea has been developed, the analysis completed, and funding identified, the work can begin and new value can be created.

A Standards and Systems database has advantages for both property managers and reports. Assimilation of new staff members and continued participation of existing staff members is essential to the cohesion of a team. A database allows all members of the team to come together to develop and promulgate the team's standards. By encouraging input from the people practicing management everyday, team interaction grows and the group makes the database realistic and useful.