Where Is In The World Is Sharon Elizabeth Kinne?

In some embodiments, reduced, delayed or eliminated MPS II symptoms in the subject after treatment is measured, for example, by a change from baseline or a stabilization in joint range of motion (JROM). In some embodiments, the delayed or reduced need for a bone marrow transplant is measured, for example, by a change from baseline or stabilization in joint range of motion (JROM). In some embodiments, withdrawal of ERT in a subject with MPS II after treatment with the methods and compositions disclosed herein is assessed by one or more of the following before and after treatment: measuring a change or stabilization in IDS activity or level in the plasma, CSF, liver or in leukocytes as between before and after treatment, in which increased IDS activity after treatment is indicative that ERT can be delayed or withdrawn ; measuring a change or stabilization in total GAG, DS GAG (e.g. GAG comprising dermatan sulfate), and/or HS GAG (e.g. GAG comprising heparan sulfate) levels (expressed as a ratio to creatinine) in the treated subject’s urine as between before and after treatment, wherein a reduction or stabilization in levels of total GAG, DS GAG and/or HS GAG after treatment is indicative that ERT can be withdrawn or delayed; measuring a change from baseline or stabilization in forced vital capacity measured by a pulmonary function test as between before and after treatment, wherein an increase or stabilization in the forced vital capacity after treatment is indicative that ERT can be withdrawn or delayed; measuring a change from base line or stabilization in distance walked as measured by the subject performing a 6 minute walk test before and after treatment to determine the change from base line due to treatment, wherein an increase or stabilization in the distance walked by the subject after treatment is indicative that ERT can be withdrawn or delayed; measuring a change from baseline or stabilization in joint range of motion (JROM) as between before and after treatment, wherein an increase or stabilization in the range of motion after treatment is indicative that ERT can be withdrawn; measuring a change from baseline or stabilization in spleen and/or liver volume as measured by MRI as between before and after treatment, wherein a decrease or stabilization in the spleen and/or liver volume after treatment is indicative that ERT can be withdrawn or delayed; measuring a change from baseline or stabilization (before treatment) in neurocognitive abilities as measured by WASI-II (Wechsler Abbreviated Scale of Intelligence, Second Edition (Shapiro et al., ibid)), WPPSI-IV (Wechsler Preschool and Primary Scale of Intelligence), or BSID-III (Bayley Scales of Infant Development), and by VABS-II (Vineland Adaptive Behavior Scales), wherein improvement or stabilization in neurocognitive abilities as between baseline (before) and after treatment are indicative that ERT can be withdrawn or delayed; and/or measuring a change from baseline in total GAG, DS GAG, and/or HS GAG levels measured in liver tissue and CSF before and after treatment, wherein a reduction or stabilization in total GAG, DS GAG and/or HS GAG levels after treatment are indicative that ERT can be withdrawn or delayed.

In some embodiments, the reduced or delayed need for ERT is measured, for example, by a change from baseline or stabilization in total GAG, DS GAG, and HS GAG levels measured in liver tissue and CSF. In some embodiments, GAG levels are used as a biochemical marker to assess treatment effect once a patient has withdrawn from ERT following treatment with the compositions disclosed herein. GAG measurements are most useful when used in conjunction with an assessment of other clinical parameters for the patient. In some embodiments, the ZFNs in the albumin-specific pair are delivered to the hepatocytes via AAV2/6 delivery wherein one AAV comprises the left ZFN (SBS-71557; SEQ ID NO:30) and another comprises the right ZFN (SBS-71728; SEQ ID NO:31). In some embodiments, the ZFN comprises two separate polynucleotides (carried on AAV vectors): SB-47171 AAV (e.g. Table 1, SEQ ID NO:9) and SB-47898 (e.g. Table 2, SEQ ID NO:12).

In some embodiments, the ZFN comprises two separate polynucleotides (carried on AAV vectors): SB-47171 AAV or SB-71557 (e.g. Table 1 or Table web cam 4, SEQ ID NO:9 or SEQ ID NO:30, respectively) and SB-47898 or SB-71728 (e.g. Table 2 or Table 5, SEQ ID NO:12 or SEQ ID NO:31, respectively). In some embodiments, the hIDS transgene donor further comprises a stop codon, for example, at the 3′ end to prevent further transcription of the albumin sequences into which the IDS transgene is inserted. In some embodiments, the hIDS transgene donor further comprises, for example, a stop codon at the 3′ end to prevent further transcription of the albumin sequences into which the IDS transgene is inserted. In some embodiments, ZFN expression is under control of a liver-specific enhancer and promoter, comprised of, for example, the human ApoE enhancer and human .alpha.1-anti-trypsin (hAAT) promoter (Miao C H et al. In some embodiments, the ApoE/hAAT promoter (e.g., SEQ ID NO:2) is specifically and highly active in hepatocytes, the intended target tissue, but is inactive in non-liver cell and tissue types; this prevents ZFN expression and activity in non-target tissues.

In some embodiments, the methods and compositions disclosed herein comprise dosing of the composition, for example, via a peripheral vein catheter. In some embodiments, the treatment using the methods and compositions as disclosed herein of the subject comprises dosing of a composition of the invention, for example, via a peripheral vein catheter. In some embodiments, any of the methods and compositions described herein may use a three component AAV system (2 AAVs for each component of a paired ZFN and 1 AAV carrying the donor), for example a composition which comprises SB-47171 AAV (e.g. Table 1), SB-47898 AAV (e.g. Table 2) and SB-IDS AAV (e.g. Table 3). In some embodiments, the composition comprises SB-71557 AAV (e.g. Table 4, SEQ ID NO:30); SB-71728 (e.g. Table 5, SEQ ID NO:31); and SB-IDS AAV (e.g. Table 3, SEQ ID NO:17). In some embodiments, the methods may further comprise assessing the ability to withdraw ERT in a subject by, for example, measuring one or more symptoms associated with MPS II, for example by assessing changes in organomegaly, hyperactivity, aggressiveness, neurologic deterioration, joint stiffness, skeletal deformities, heart valve thickening, hearing loss, hernias, and/or upper respiratory infections in the subject following administration of the transgene and ZFN(s), wherein if the measurements demonstrate that one or more of these (MPS II) symptoms are reduced, delayed or eliminated by the compositions and methods disclosed herein such that ERT is no longer needed.

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