Recent studies in non-human primates administered recombinant adeno-associated viruses (rAAVs) have shown lesions in the dorsal root ganglia (DRG) of unknown pathogenesis. In this study, rAAV9s manufactured using different purification methods alongside a non-expressing Null AAV9 vector was administered to groups of cynomolgus monkeys followed by neuropathological evaluation after 4 weeks. Lesions, including neuronal degeneration, increased cellularity, and nerve fiber degeneration, were observed in the DRG, regardless of purification methods. Animals did not develop any neurological signs throughout the study, and there was no loss of function observed in neuro-electrophysiological endpoints or clear effects on intraepidermal nerve fiber density. However, magnetic resonance imaging (MRI) of animals with axonopathy showed an increase in short tau inversion recovery (STIR) intensity and decrease in fractional anisotropy. In animals administered the Null AAV9 vector, DRG lesions were not observed despite vector DNA being detected in the DRG at levels equivalent to or greater than rAAV9-treated animals. This study further supports that DRG toxicity is associated with transgene overexpression in DRGs, with particular sensitivity at the lumbar and lumbosacral level. The data from this study also showed that the nerve fiber degeneration did not correlate with any functional effect on nerve conduction but was detectable by MRI.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

[²¹²Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. ²¹²Pb has an elementally matched gamma-emitting isotope ²⁰³Pb; thus, [²⁰³Pb]VMT01 can be used as an imaging surrogate for [²¹²Pb]VMT01. [²¹²Pb]VMT01 human serum stability studies have demonstrated retention of the ²¹²Bi daughter within the chelator following beta emission of parent ²¹²Pb. However, the subsequent alpha emission from the decay of ²¹²Bi into ²⁰⁸Tl results in the generation of free ²⁰⁸Tl. Due to the 10.64-hour half-life of ²¹²Pb, accumulation of free ²⁰⁸Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for [²¹²Pb]VMT01 and the impact of free ²⁰⁸Tl in the injectate on human tissue absorbed doses. Human [²¹²Pb]VMT01 tissue absorbed doses were estimated from murine [²⁰³Pb]VMT01 biodistribution data, and human biodistribution values for ²⁰¹Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free ²⁰⁸Tl. Results indicate that the dose-limiting tissues for [²¹²Pb]VMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGy_{RBE = 5}/MBq. The estimated percent increase in absorbed doses from free ²⁰⁸Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free ²⁰⁸Tl result in a percent increase of no more than 1.2% over [²¹²Pb]VMT01 in any organ or tissue. This latter finding indicates that free ²⁰⁸Tl in the [²¹²Pb]VMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.