Safety Findings of Dosing Gene Therapy Vectors in NHP With Pre-existing or Treatment-Emergent Anti-capsid Antibodies.

Replication-incompetent adeno-associated virus (AAV)-based vectors are nonpathogenic viral particles used to deliver therapeutic genes to treat multiple monogenic disorders. AAVs can elicit immune responses; thus, one challenge in AAV-based gene therapy is the presence of neutralizing antibodies against vector capsids that may prevent transduction of target cells or elicit adverse findings. We present safety findings from two 12-week studies in nonhuman primates (NHPs) with pre-existing or treatment-emergent antibodies.

Young mice administered adult doses of AAV5-hFVIII-SQ achieve therapeutic factor VIII expression into adulthood.

Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) gene transfer provided reduced bleeding for adult clinical trial participants with severe hemophilia A. However, pediatric outcomes are unknown. Using a mouse model of hemophilia A, we investigated the effect of vector dose and age at treatment on transgene production and persistence.

Lack of germline transmission in male mice following a single intravenous administration of AAV5-hFVIII-SQ gene therapy.

Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus serotype five gene therapy under investigation for the treatment of hemophilia A. Herein, we assessed the potential for germline transmission of AAV5-hFVIII-SQ in mice. Male B6.

The Impact of Pre-existing Immunity on the Non-clinical Pharmacodynamics of AAV5-Based Gene Therapy.

Adeno-associated virus (AAV)-based vectors are widely used for gene therapy, but the effect of pre-existing antibodies resulting from exposure to wild-type AAV is unclear. In addition, other poorly defined plasma factors could inhibit AAV vector transduction where antibodies are not detected. To better define the relationship between various forms of pre-existing AAV immunity and gene transfer, we studied valoctocogene roxaparvovec (BMN 270) in cynomolgus monkeys with varying pre-dose levels of neutralizing anti-AAV antibodies and non-antibody transduction inhibitors.

Metabolic and ventilatory acclimatization to cold stress in house sparrows (Passer domesticus).

Passerines that overwinter in temperate climates undergo seasonal acclimatization that is characterized by metabolic adjustments that may include increased basal metabolic rate (BMR) and cold-induced summit metabolism (M(sum)) in winter relative to summer. Metabolic changes must be supported by equivalent changes in oxygen transport. While much is known about the morphology of the avian respiratory system, little is known about respiratory function under extreme cold stress.