BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age ,2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age #8 months. METHODS:In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio.RESULTS: In children #6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with g glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and g glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS:In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.

Background Segmental bone loss remains a challenging clinical problem. A frequent mitigating factor is inadequate blood supply. Small molecules that activate the hypoxia inducible factor pathway (HIF) can be used to stimulate angiogenesis. We investigated an approach to promote healing using angiogenic and osteogenic compounds in combination with a biodegradable, weight bearing scaffold. Methods Adult rats underwent removal of a 5mm segment of femur stabilized by a cylindrical biodegradable implant and intramedullary fixation. Treatment groups included (1) saline (negative control), (2) desferrioxamine ((DFO), a HIF activator), (3) low dose rhBMP-2 (5µg), (4) DFO and low dose rhBMP-2 (5µg) or (5) rh-BMP-2 (10µg). Angiography was used to evaluate vascularity. Bone healing was assessed by radiographs, µCT, histology and biomechanical testing. Results Increased vascularity was seen at 6 weeks in the DFO treatment group. There appeared to be increased bone bridging as assessed by radiographic scores and µCT in the BMP groups, although the quantification of bone volume did not show statistically significant differences. Biomechanical testing revealed improved stiffness in the treatment groups. Conclusions DFO improved angiogenesis and stiffness of bone healing in segmental defects. BMP improved radiographic scores and stiffness. Use of angiogenic compounds in segmental bone loss is promising. Clinical Relevance Activation of the HIF pathway may prove useful for bone defects, particularly where impaired blood supply exists. The low cost approach could be useful in segmental bone defects clinically.

Melatonin was measured over 24 hr in the eyestalks of Uca pugilator by means of radioimmunoassay; crabs were acclimatized either to a LD 12:12 photoperiod or constant darkness. A significant peak occurred at 13.00 hr in the LD 12:12 crabs. A photophase peak in melatonin has only been reported in one other species, also a crustacean. In constant darkness, two melatonin peaks occurred, one at 16.00 hr and the other 12 hr later; these results suggest that the melatonin cycle is a true circadian rhythm. HPLC with ultraviolet-visible detection was used to confirm the identity of melatonin immunoactivity. The influence of melatonin on regeneration of the walking legs was also examined: eyestalks were either removed or left intact, and limb bud length was measured every other day for at least 17 days in control and melatonin-treated crabs (60 microg ml(-1) seawater). Melatonin significantly increased the rate of limb regeneration in both eyestalk-intact and eyestalk-removed groups; this is contrary to results of regeneration studies in other phyla, in which similar melatonin concentrations inhibited regeneration.

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