Molecular Therapy - Methods & Clinical Development

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Molecular Therapy - Methods & Clinical Development

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Molecular Therapy - Methods & Clinical Development Systemic gene transfer reveals distinctive muscle transduction profile of tyrosine mutant AAV-1, -6, and -9 in neonatal dogs Chady H Hakim, Yongping Yue, Jin-Hong Shin, Regina R Williams, Keqing Zhang, Bruce F Smith, Dongsheng Duan Molecular Therapy - Methods & Clinical Development Volume 1, (January 2014) DOI: 10.1038/mtm.2014.2 Copyright © 2014 American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 Systemic Y731F AAV-9 injection in a newborn puppy (Monica #4, 1.36 × 1011 vg/g of SPc5-12.AP) resulted in bodywide skeletal muscle transduction. Representative photomicrographs of AP histochemical staining in (a) skeletal muscles, (d) heart muscles, and (g) internal organs. Scale bar = 100 µm and it applies to all images. AP activity quantification results are shown for (b) skeletal muscles, (e) heart muscles, and (h) internal organs. The AAV genome copy number is shown for (c) skeletal muscles, (f) heart muscles, and (i) internal organs. AAV, adenoassociated virus; AP, alkaline phosphatase; BB, biceps brachii; BR, brain; CS, cranial sartorius; CT, cranial tibialis; DI, diaphragm; KI, kidney; LA, left atrium; LI, liver; LU, lung; LV, left ventricle; RA, right atrium; RV, right ventricle. Molecular Therapy - Methods & Clinical Development 2014 1, DOI: (10.1038/mtm.2014.2) Copyright © 2014 American Society of Gene & Cell Therapy Terms and Conditions

Figure 2 Transduction profile of Rover, a puppy that received 0.75 × 1011 vg/g of RSV.AP Y731F AAV-6 at birth. Representative photomicrographs of AP histochemical staining in (a) skeletal muscles, (d) heart muscles, and (g) internal organs. Scale bar = 100 µm and it applies to all images. AP activity quantification results are shown for (b) skeletal muscles, (e) heart muscles, and (h) internal organs. The AAV genome copy number is shown for (c) skeletal muscles, (f) heart muscles, and (i) internal organs. AAV, adenoassociated virus; AP, alkaline phosphatase; BB, biceps brachii; BR, brain; CS, cranial sartorius; CT, cranial tibialis; DI, diaphragm; KI, kidney; LA, left atrium; LI, liver; LU, lung; LV, left ventricle; RV, right ventricle; RA, right atrium. Molecular Therapy - Methods & Clinical Development 2014 1, DOI: (10.1038/mtm.2014.2) Copyright © 2014 American Society of Gene & Cell Therapy Terms and Conditions

Figure 3 Transduction profile of Monica #6, a puppy that received 1.57 × 1011 vg/g of RSV.AP Y731F AAV-6 at birth. Representative photomicrographs of AP histochemical staining in (a) skeletal muscles, (d) heart muscles, and (g) internal organs. Scale bar = 100 µm and it applies to all images. AP activity quantification results are shown for (b) skeletal muscles, (e) heart muscles, and (h) internal organs. The AAV genome copy number is shown for (c) skeletal muscles, (f) heart muscles, and (i) internal organs. AAV, adenoassociated virus; AP, alkaline phosphatase; BB, biceps brachii; BR, brain; CS, cranial sartorius; CT, cranial tibialis; DI, diaphragm; KI, kidney; LA, left atrium; LI, liver; LU, lung; LV, left ventricle; RV, right ventricle; RA, right atrium. Molecular Therapy - Methods & Clinical Development 2014 1, DOI: (10.1038/mtm.2014.2) Copyright © 2014 American Society of Gene & Cell Therapy Terms and Conditions

Figure 4 Transduction profile of Peter, a puppy that received 1.47 × 1011 vg/g of SPc5-12.AP Y731F AAV-6 at birth and harvested at 9.2 months later. Representative photomicrographs of AP histochemical staining in (a) skeletal muscles, (d) heart muscles, and (g) internal organs. Scale bar = 100 µm and it applies to all images. AP activity quantification results are shown for (b) skeletal muscles, (e) heart muscles, and (h) internal organs. The AAV genome copy number is shown for (c) skeletal muscles, (f) heart muscles, and (i) internal organs. AAV, adenoassociated virus; AP, alkaline phosphatase; BB, biceps brachii; CS, cranial sartorius; CT, cranial tibialis; DI, diaphragm; LV, left ventricle; RV, right ventricle; LA, left atrium; RA, right atrium; LI, liver; KI, kidney; LU, lung; and BR, brain. Molecular Therapy - Methods & Clinical Development 2014 1, DOI: (10.1038/mtm.2014.2) Copyright © 2014 American Society of Gene & Cell Therapy Terms and Conditions

Figure 5 Neonatal intravascular Y445F/Y731F AAV-1 injection in a newborn puppy (Bing, 1.87 × 1011 vg/g of SPc5-12.AP) resulted in robust transduction in the heart and skeletal muscle. Representative photomicrographs of AP histochemical staining in (a) skeletal muscles, (d) heart muscles, and (g) internal organs. Scale bar = 100 µm and it applies to all images. AP activity quantification results are shown for (b) skeletal muscles, (e) heart muscles, and (h) internal organs. The AAV genome copy number is shown for (c) skeletal muscles, (f) heart muscles, and (i) internal organs. AAV, adenoassociated virus; AP, alkaline phosphatase; BB, biceps brachii; CS, cranial sartorius; CT, cranial tibialis; DI, diaphragm; LV, left ventricle; RV, right ventricle; LA, left atrium; RA, right atrium; LI, liver; KI, kidney; LU, lung; and BR, brain. Molecular Therapy - Methods & Clinical Development 2014 1, DOI: (10.1038/mtm.2014.2) Copyright © 2014 American Society of Gene & Cell Therapy Terms and Conditions