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In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.

Usher syndrome type 1B is a combined deaf-blindness condition caused by mutations in the MYO7A gene. Loss of functional myosin VIIa in the retinal pigment epithelia (RPE) and/or photoreceptors leads to blindness. We evaluated the impact of subretinally delivered UshStat, a recombinant EIAV-based lentiviral vector expressing human MYO7A, on photoreceptor function in the shaker1 mouse model for Usher type 1B that lacks a functional Myo7A gene. Subretinal injections of EIAV-CMV-GFP, EIAV-RK-GFP (photoreceptor specific), EIAV-CMV-MYO7A (UshStat) or EIAV-CMV-Null (control) vectors were performed in shaker1 mice. GFP and myosin VIIa expression was evaluated histologically. Photoreceptor function in EIAV-CMV-MYO7A treated eyes was determined by evaluating α-transducin translocation in photoreceptors in response to low light intensity levels, and protection from light induced photoreceptor degeneration was measured. The safety and tolerability of subretinally delivered UshStat was evaluated in macaques. Expression of GFP and myosin VIIa was confirmed in the RPE and photoreceptors in shaker1 mice following subretinal delivery of the EIAV-CMV-GFP/MYO7A vectors. The EIAV-CMV-MYO7A vector protected the shaker1 mouse photoreceptors from acute and chronic intensity light damage, indicated by a significant reduction in photoreceptor cell loss, and restoration of the α-transducin translocation threshold in the photoreceptors. Safety studies in the macaques demonstrated that subretinal delivery of UshStat is safe and well-tolerated. Subretinal delivery of EIAV-CMV-MYO7A (UshStat) rescues photoreceptor phenotypes in the shaker1 mouse. In addition, subretinally delivered UshStat is safe and well-tolerated in macaque safety studies These data support the clinical development of UshStat to treat Usher type 1B syndrome.

Leishmania are obligatory intracellular parasites in mammalian macrophages that gain entry by receptormediated phagocytosis. Their major cell surface glycoconjugate, lipophosphoglycan (LPG), has been implicated in this process. A monoclonal antibody specific for Leishmania major LPG (WIC 79.3), which has been shown to block promastigote attachment to macrophages, was used to identify a macrophage-binding determinant of LPG. WIC 79.3 bound exclusively to the phosphorylated repeats of LPG and not to the saccharide core or lipid anchor. Furthermore, the epitope recognized by WIC 79.3 mapped to the phosphorylated oligosaccharide P5b, P04-6[Gal(g31-3)Gal(fi1-3)Gal(fl1-3)]Gal(131-4)Man(al-, which is unique to the LPG of promastigotes of L.major. Phosphorylated oligosaccharides P3, 3)JGal(f1l-4)Man(a1-, and P4b, LPGs form a polymorphic family of similar, but antigenically and structurally distinct, molecules present on all Leishmania species. The LPG molecule has a tripartite structure consisting of a series of phosphorylated oligosaccharide repeats (PORs) and a conserved phosphorylated saccharide core attached to a conserved, unusual lyso-alkyl phosphatidylinositol anchor ( Fig. 1; for review, see ref. 10). The PORs consist of a backbone of phosphodiester-linked disaccharide repeats [PO4-6Gal(31-4)Man(a1-], which is conserved in all species (9, 11). Variability between species involves side chain branches of varying complexity extending out from this common backbone (9, 11). Leishmania donovani displays the minimal structure with no branching, whereas L. major has the most complex, with the backbone sequence substituted with mono-, di-, tri-, and tetrasaccharide side chains consisting of combinations of galactose, arabinose, and glucose residues ( Fig. 1; ref. 9 tTo whom reprint requests should be addressed. 6The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.