In comparison to our standard 3�� per week schedule,histopathologic improvement was less pronounced with reduced treat ment frequencies.Next,we make it clear tested different administration routes since IP delivery is not feasible for DMD patients.While our previous findings showed that IP delivery of NBD was effective in significantly reducing muscle inflammation and necrosis,no Inhibitors,Modulators,Libraries such improvements were observed following subcutaneous dosing.In contrast,delivering NBD by intra venous dosing for 4 weeks using a VAP,which allowed repeated dosing through a catheter line,resulted in significant histopathologic improvement in mdx skel etal muscles.This suggested that IV delivery might be a suitable route for dosing NBD in larger species.

This point was further supported by PK mea surements,which showed a dose dependent increase of NBD in the blood of normal mice Inhibitors,Modulators,Libraries following single IV injections of the peptide at 2 and 10 mg kg.Establishing a treatment paradigm Inhibitors,Modulators,Libraries for GRMD dogs Having established a treatment regimen that provides ef ficacy of NBD in mice,we next asked whether such ther apy could be applied to a larger animal model of DMD.PK studies after IV delivery of NBD to normal beagle dogs showed there was a dose dependent increase of NBD following injections of 2 and 10 mg kg of peptide.This PK profile was com parable to that of mice,suggesting that the murine dos ing regimen would extrapolate to dogs.In addition,normal hematology and serum chemistry profiles were noted following a single IV injection of NBD in normal dogs.

Based on our collective data,a preclinical trial in GRMD dogs was initiated with four primary outcomes,skeletal muscle function,MRI of pelvic limb muscles,histopathologic features of skeletal muscles,and safety.Juvenile GRMD and wild type dogs at 2 months Inhibitors,Modulators,Libraries of age were treated for 4 months by IV infusions,3�� weekly,at 10 mg Kg.Re sults were compared with those collected from untreated GRMD and wild type Inhibitors,Modulators,Libraries dogs through a separate,natural history study.NBD treatment enhances GRMD muscle function and reduces postural abnormalities TTJ force We have previously assessed force generated by TTJ flexion and extension in both natural history and pre clinical studies.Data from a recently completed natural history study were compared with results from NBD treated GRMD dogs at 6 months of age.Force values,corrected for body weight,were used as the primary outcome parameter to be consistent with the prior studies.

Presumably owing to changes in in strumentation and methodology,these natural history data differ somewhat from our previously pub lished results,making direct comparison difficult.Im portantly,data from the control natural history and NBD treated dogs reported here were collected using the same instrumentation and over a similar time inhibitor manufacture frame.GRMD dogs treated with NBD for 4 months exhibited a significant 73% increase in extension force when com pared to untreated GRMD dogs.