Granted Patent
B2
US 12,540,334 · App. 17/613,612 · Granted Feb 3, 2026
Gene therapy for Alzheimer's disease
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present disclosure provides, among other things, human codon-optimized sequences encoding presenilin 1, and methods for using the sequences in gene therapy to treat neurodegenerative diseases including, but not limited to Alzheimer's disease, frontotemporal dementia, frontotemporal lobar degeneration, Pick's disease, Lewy body dementia, memory loss, and cognitive impairment including mild cognitive impairment (MCI).
Claims (21)
1 . A composition comprising a human codon-optimized polynucleotide encoding a human presenilin 1 (PSEN1), wherein the human codon-optimized polynucleotide encoding a human PSEN1 is at least 95% identical to SEQ ID NO:9, with at least one codon optimized with respect to wild type.
2 . The composition claim 1 , wherein the human codon-optimized polynucleotide encoding a human PSEN1 comprises SEQ ID NO:9.
3 . The composition of claim 1 , which is associated with an exosome or lipid-based nanoparticle (LNP).
4 . A composition comprising a vector for expression of human PSEN1 in a cell, comprising the human codon-optimized polynucleotide of claim 1 , operably linked to a promoter.
5 . The composition of claim 4 , wherein the vector is a viral vector.
6 . The composition of claim 5 , wherein the viral vector is an adeno-associated viral (AAV) vector.
7 . The composition of claim 6 , wherein the AAV vector is AAV9 or AAVrh10.
8 . The composition of claim 5 , wherein the viral vector is a lentiviral vector or a retroviral vector.
9 . The composition of claim 4 , wherein the promoter is a pan neuronal promoter.
10 . The composition of claim 9 , wherein the pan neuronal promoter is a synapsin I promoter.
11 . The composition of claim 4 , wherein the promoter is a neuron subtype-specific promoter.
12 . The composition of claim 11 , wherein the neuron subtype-specific promoter is an alpha-calcium/calmodulin kinase 2A promoter.
13 . A method of treating a neurodegenerative disease, disorder, or condition, the method comprising administering to a human subject in need of treatment a composition of claim 1 , wherein the subject has one or more mutations in at least one allele of PSEN1, wherein the neurodegenerative disease, disorder or condition is Alzheimer's disease.
14 . The method of claim 13 , wherein the Alzheimer's disease is familial Alzheimer's disease.
15 . The method of claim 13 , wherein the subject has a E280A, Y115H, L166P, C410Y, Aex9, G548, D257A, R278I, L435F, G384A, or L392Vmutation in the PSEN1 gene, or a N141I, G206A, H163R, A79V, S290C, A260P, A426P, A431E, R269H, L271V, C1410Y, E280G, P264L, E185D, L235V, or M146V mutation in the PSEN1 gene.
16 . The method of claim 13 , wherein the Alzheimer's disease is sporadic Alzheimer's disease.
17 . The method of claim 13 , wherein the Alzheimer's disease is late-onset or early-onset Alzheimer's disease.
18 . The method of claim 13 , wherein the neurodegenerative disease, disorder or condition is frontotemporal dementia, memory loss, cognitive decline or impairment.
19 . The method of claim 18 , wherein the cognitive impairment is mild cognitive impairment (MCI).
20 . The method of claim 13 , wherein the composition is administered to the CNS of the subject in need of treatment.
21 . The method of claim 20 , wherein the polynucleotide encoding PSEN1 and/or PSEN2 gene or mRNA is administered to the CNS via intravenous delivery, via intrathecal delivery, via intracisternal delivery, via intracerebroventricular delivery, or via stereotactic injection into certain areas of the brain, optionally into cisterna magna, cerebral ventricles, or lumbar intrathecal space, or via direct injection into hippocampus or cortical areas.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 5, 2026
From: KELLEHER, RAYMOND J., III
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 073363/0777 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 15, 2023
From: SHEN, JIE
To: THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Reel/Frame 063099/0992 →
Continuity (2)
Provisional Application
62852716
· May 24, 2019
References Cited (296)
US 5328470A
· Nabel et al.
· 1994
[cited by applicant]
US 5658776A
· Flotte et al.
· 1997
[cited by applicant]
US 6020143A
· St. George-Hyslop et al.
· 2000
[cited by applicant]
US 6180613B1
· Kaplitt et al.
· 2001
[cited by applicant]
US 6395960B1
· St. George-Hyslop et al.
· 2002
[cited by applicant]
US 6503888B1
· Kaplitt et al.
· 2003
[cited by applicant]
US 6686449B2
· Carter et al.
· 2004
[cited by applicant]
US 6783955B2
· Arvizu
· 2004
[cited by applicant]
US 6979537B2
· McCarthy et al.
· 2005
[cited by applicant]
US 7271313B2
· Shen
· 2007
[cited by applicant]
US 7498316B2
· Xu et al.
· 2009
[cited by applicant]
US 7709616B2
· Bentwich et al.
· 2010
[cited by applicant]
US 8129334B2
· Dewji et al.
· 2012
[cited by applicant]
US 9512191B2
· Dewji et al.
· 2016
[cited by applicant]
US 9956271B2
· Guild et al.
· 2018
[cited by applicant]
US 20020082211A1
· Arvizu et al.
· 2002
[cited by applicant]
US 20030065141A1
· Carter et al.
· 2003
[cited by applicant]
US 20180094280A1
· Kutner et al.
· 2018
[cited by applicant]
US 20230136245A1
· Gannon et al.
· 2023
[cited by applicant]
CN 103282374A
· 2013
[cited by applicant]
CN 103816540A
· 2014
[cited by applicant]
CN 106604988A
· 2017
[cited by applicant]
CN 107614008A
· 2018
[cited by applicant]
EP 0826042B1
· 2008
[cited by applicant]
EP 2010663
· 2009
[cited by applicant]
JP H11504214A
· 1999
[cited by applicant]
JP 2013509890
· 2013
[cited by applicant]
JP 2013107890
· 2013
[cited by applicant]
JP 2016523835
· 2016
[cited by applicant]
JP 2018510615A
· 2018
[cited by applicant]
JP 2021525245A
· 2021
[cited by applicant]
WO WO199500655
· 1995
[cited by applicant]
WO WO199511984
· 1995
[cited by applicant]
WO WO199527071
· 1995
[cited by applicant]
WO WO2000003248A1
· 2000
[cited by applicant]
WO WO2001051671
· 2001
[cited by applicant]
WO WO2005003350A2
· 2005
[cited by applicant]
WO WO2005037226A2
· 2005
[cited by applicant]
WO WO2005116250A2
· 2005
[cited by applicant]
WO WO2009042727
· 2009
[cited by applicant]
WO WO2015006743A1
· 2015
[cited by applicant]
WO WO2016209654A1
· 2016
[cited by applicant]
WO WO2017191274
· 2017
[cited by applicant]
WO WO2017205767A1
· 2017
[cited by applicant]
WO WO2018045022A1
· 2018
[cited by applicant]
WO WO2018140532
· 2018
[cited by applicant]
WO WO2018175443A1
· 2018
[cited by applicant]
WO WO2018222890
· 2018
[cited by applicant]
WO WO2019028306
· 2019
[cited by applicant]
WO WO2019028306A2
· 2019
[cited by examiner]
WO WO2019226832
· 2019
[cited by applicant]
WO WO2021155296
· 2021
[cited by applicant]
Yang Ge, Yu Kun , Kaitatzi Christina-Symina, Singh Abhilasha, Labahn Jorg. Influence of solubilization and AD mutations on stability and structure of human presenilins. Nature: Scientific Reports, 7:17970 (Year: 2017).
[cited by examiner]
Sun Linfeng, Zhou Rui, Yang Guanghui, Shi Yigong. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of ABeta42 and ABeta40 peptides by gamma-secretase. Proceedings of the National Academy o…
[cited by examiner]
Dittgen Tanjew, Nimmerjahn Axel, Komai Shoji, Licnerski Pawel, Waters Jack, Margrie Troy W, Helmchen Fritjof, Denk Winfried, Brecht Michael, Osten Pavel. Lentivirus-based genetic manipulations of cortical neurons and th…
[cited by examiner]
Honda Makota, Minami Itsunari, Tooi Norie, Morone Nobuhiro, Nishioka Hisae, Uemura Kengo, Kinoshita Ayae, Heuser John E, Nakatsuji Norio, Kazuhiro Aiba. The modeling of Alzheimer's disease by the overexpression of mutan…
[cited by examiner]
Rumiana Tenchov, Robert Bird, Allison E. Curtze and Qiongqiong Zhou. Lipid Nanoparticles-From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement. ACSNano, 15, 16982-17015 (Year: 2021).
[cited by examiner]
Honda et al. The modeling of Alzheimer's disease by the overexpression of mutant Presenilin 1 in human embryonic stem cells (Year: 2016).
[cited by examiner]
Bryan et al., “Implications of protein fold switching,” Current Opinion in Structural Biology, 2013, 2(23):314-6.
[cited by applicant]
Bulcha et al., “Viral vector platforms within the gene therapy landscape,” Signal Transduction and Targeted Therapy, Feb. 2021, 6(1):53, 24 pages.
[cited by applicant]
Chávez-Gutiérrez et al., “Mechanisms of neurodegeneration—Insights from familial Alzheimer's disease,” Seminars in Cell & Developmental Biology, Sep. 2020, (105):75-85.
[cited by applicant]
Cruz et al., “Protein function prediction,” Functional Genomics: Methods and Protocols, 3rd edition, Aug. 2018, 55, 22 pages.
[cited by applicant]
Hur, “γ-Secretase in Alzheimer's disease,” Experimental & Molecular Medicine, Apr. 2022, 54(4):433, 14 pages.
[cited by applicant]
Ingusci et al., “Gene therapy tools for brain diseases,” Frontiers in Pharmacology, Jul. 2019, 10:724, 19 pages.
[cited by applicant]
Kabir et al., “Exploring the role of PSEN mutations in the pathogenesis of Alzheimer's disease,” Neurotoxicity Research, Dec. 2020, 38:833-49.
[cited by applicant]
Kotterman et al., “Engineering adeno-associated viruses for clinical gene therapy,” Nature Reviews Genetics, Jul. 2014, 15(7):445, 18 pages.
[cited by applicant]
Lenzi et al., Gene Transfer Research: The Evolution of Clinical Science, NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protoc…
[cited by applicant]
Maqbool et al., “The substrate-binding protein in bacterial ABC transporters: dissecting roles in the evolution of substrate specificity,” Biochemical Society Transactions, Oct. 2015, 43(5):1011-7.
[cited by applicant]
Shim et al., “Nonviral delivery systems for cancer gene therapy: strategies and challenges,” Current Gene Therapy, Feb. 2018, 18(1):3-20.
[cited by applicant]
Stepanichev, “Gene editing and Alzheimer's disease: is there light at the end of the tunnel?,” Frontiers in Genome Editing, Jun. 2020, 2:4, 10 pages.
[cited by applicant]
Sudhakar et al., Gene therapy for neurodegenerative diseases, Neurotherapeutics, Jan. 2019, 16(1):166-75.
[cited by applicant]
AU Office Action in Australian Appln. No. 2020285638, mailed on May 1, 2025, 4 pages.
[cited by applicant]
Diss et al., “The genetic landscape of a physical interaction,” Elife, Apr. 2018, 7:e32472, 31 pages.
[cited by applicant]
Dryja et al., “Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa,” New England Journal of Medicine, Nov. 1990, 323(19):1302-7.
[cited by applicant]
EP Office Action in European Appln. No. 19808081.4, mailed on Apr. 23, 2025, 6 pages.
[cited by applicant]
Felsenstein et al., “Nov. 1, 2003: Endogenous cholesterol metabolites as potential Alzheimer's therapeutics,” Alzheimer's & Dementia, Jul. 2012, 8(4S Part 3):P104-5.
[cited by applicant]
GenBank Accession No. NM 000021.3, “
[cited by applicant]
GenBank Accession No. NM 000447.2, “
[cited by applicant]
GenBank Accession No. NM 007318.2, “
[cited by applicant]
GenBank Accession No. NM_012486.2, “
[cited by applicant]
JP Japanese Office Action in Japanese Appln. No. 2020-565341, Apr. 4, 2023, 11 pages (with English translation).
[cited by applicant]
Wang et al., “Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology,” Journal of Biological Chemistry, Jun. 2006, 281(22):15330-6.
[cited by applicant]
CN Office Action in Chinese Appln. No. 201980049127.3, mailed on Oct. 30, 2023, 26 pages (with English translation).
[cited by applicant]
EP Partial European Search Report in European Appln. No. 20893982.7, mailed on Nov. 15, 2023, 14 pages.
[cited by applicant]
NCBI sequence NM_000021.3, “
[cited by applicant]
NCBI reference sequence : NM_007318.2, “
[cited by applicant]
Wang et al., “Visualization of Alzheimer's disease related α-/β-/γ-secretase ternary complex by bimolecular fluorescence complementation based fluorescence resonance energy transfer,” Frontiers in Molecular Neuroscience…
[cited by applicant]
CN Office Action in Chinese Appln. No. 201980049127.3, mailed on Apr. 25, 2024, 9 pages (with English translation).
[cited by applicant]
D'Argenio et al., “New insights into the molecular bases of familial Alzheimer's disease,” Journal of Personalized Medicine, Apr. 2020, 10(2):26, 14 pages.
[cited by applicant]
Deaton et al., “Presenilin 1 regulates membrane homeostatic pathways that are dysregulated in Alzheimer's disease,” Journal of Alzheimer's Disease, Jan. 2020, 77(3):961, 25 pages.
[cited by applicant]
EP Extended European Search Report in European Appln. No. 20893982.7, mailed on May 2, 2024, 14 pages.
[cited by applicant]
Götz et al., “Rodent models for Alzheimer disease,” Nature Reviews Neuroscience, Oct. 2018, 19(10):583-98.
[cited by applicant]
Hudry et al., “Therapeutic AAV gene transfer to the nervous system: a clinical reality,” Neuron, Mar. 2019, 101(5):839, 26 pages.
[cited by applicant]
John et al., “Synaptic basis of Alzheimer's disease: Focus on synaptic amyloid beta, P-tau and mitochondria,” Ageing Research Reviews, Jan. 2021, 65:101208, 35 pages.
[cited by applicant]
Yang et al., “Presenilin-1 (PSEN1) mutations: clinical phenotypes beyond Alzheimer's disease,” International Journal of Molecular Sciences, May 2023, 24(9):8417, 21 pages.
[cited by applicant]
CN Office Action in Chinese Appln. No. 202080052274.9, mailed on Mar. 12, 2024, 9 pages (with English translation).
[cited by applicant]
EP Extended European Search Report in European Appln. No. 21747911.2, mailed on Mar. 14, 2024, 11 pages.
[cited by applicant]
GenBank Accession No. NM_000021.4, “
[cited by applicant]
JP Office Action in Japanese Appln. No. 2020-565341, mailed on Jan. 9, 2024, 14 pages (with English translation).
[cited by applicant]
Millington-Ward et al., “Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa,” Molecular Therapy, Apr. 2011, 19(4):642-9.
[cited by applicant]
Montenegro et al., “Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in Psen mutant mice,” Proceedings of the National Academy of Sciences, Oct. 2023, 12…
[cited by applicant]
Pelletier et al., “RNA based gene therapy for dominantly inherited diseases,” Current Gene Therapy, Feb. 2006, 6(1):131-46.
[cited by applicant]
Pimenova et al., “Novel presenilin 1 and 2 double knock-out cell line for in vitro validation of PSEN1 and PSEN2 mutations,” Neurobiology of Disease, Feb. 2020, 138, 24 pages.
[cited by applicant]
Sierant et al., “Specific silencing of L392V PSEN1 mutant allele by RNA interference,” International Journal of Alzheimer's Disease, Jan. 2011, vol. 2011, 14 pages.
[cited by applicant]
Trochet et al., “Therapy for dominant inherited diseases by allele-specific RNA interference: successes and pitfalls,” Current Gene Therapy, Oct. 2015, 15(5):503, 27 pages.
[cited by applicant]
Uniprot Accession No. P49768.1, “Presenilin-1,” Oct. 1, 1996, 55 pages.
[cited by applicant]
Uniprot Accession No. P49810.1, “Presenilin-2,” Oct. 1, 1996, 14 pages.
[cited by applicant]
Castle et al., “Controlling AAV tropism in the nervous system with natural and engineered capsids,” Gene Therapy for Neurological Disorders: Methods and Protocols, Jan. 2016, 133-49.
[cited by applicant]
CN Office Action in Chinese Appln. No. 201980049127.3, mailed on Jul. 16, 2024, 14 pages (with English translation).
[cited by applicant]
Haery et al., Adeno-associated virus technologies and methods for targeted neuronal manipulation. Frontiers in Neuroanatomy, Nov. 2019, 13:493120, 16 pages.
[cited by applicant]
IL Office Action in Israeli Appln. No. 278813, mailed on Jul. 21, 2024, 4 pages (English translation).
[cited by applicant]
JP Office Action in Japanese Appln. No. 2021-569550, mailed on May 28, 2024, 8 pages (with English translation).
[cited by applicant]
Bird et al., “Wide range in age of onset for chromosome 1-related familial Alzheimer's disease,” Annals of Neurology, Dec. 1996, 40(6):932-936.
[cited by applicant]
Cai et al., “Mutations in presenilin 2 and its implications in Alzheimer's disease and other dementia-associated disorders,” Clinical Interventions in Aging, Jul. 2015, 10:1163-1172.
[cited by applicant]
Chen et al., “Enhancing the Utility of Adeno-Associated Virus Gene Transfer through Inducible Tissue-Specific Expression,” Human Gene Therapy Methods, Aug. 2013, 24(4):270-278.
[cited by applicant]
Colin et al., “Engineered lentiviral vector targeting astrocytes in vivo,” Glia, Apr. 2009, 57(6):667-79.
[cited by applicant]
Dana et al., “Molecular mechanisms and biological functions of siRNA,” International Journal of Biomedical Science, Jun. 2017, 13(2):48-57.
[cited by applicant]
Elbashir et al., “Duplexes of 21±nucleotide RNAs mediate RNA interference in cultured mammalian cells,” Nature, May 2001, 411:494-498.
[cited by applicant]
Gray et al., “Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors,” Human Gene Therapy, Sep. 2011, 22:1143-1…
[cited by applicant]
Karabinos et al., “Essential roles for four cytoplasmic intermediate filament proteins in Caenorhabditis elegans development,” Proceedings of the National Academy of Sciences of the United States of America, Jul. 2001, …
[cited by applicant]
Lanoiselée et al., “APP, PSEN1, and PSEN2 mutations in early onset Alzheimer disease: A genetic screening study of familial and sporadic cases,” PLOS Medicine, Mar. 2017, 14(3):e102270, 16 pages.
[cited by applicant]
Ling et al., “Enhanced transgene expression from recombinant single-stranded D-sequence-substituted adeno-associated virus vectors in human cell lines in vitro and in murine hepatocytes in vivo,” Journal of Virology, Ja…
[cited by applicant]
Matsushita et al., “Adeno-associated virus vectors can be efficiently produced without helper virus,” Gene Therapy, Jul. 1998, 5:938-945.
[cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2020/062394, mailed on May 17, 2022, 7 pages.
[cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2021/015911, mailed on Jul. 28, 2022, 9 pages.
[cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2021/015911, mailed on Jun. 30, 2021, 14 pages.
[cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2020/062394, mailed on Apr. 28, 2021, 15 pages.
[cited by applicant]
Perez-Pinera et al., “RNA-guided gene activation by CRISPR-Cas9-based transcription factors,” Oct. 2013, Nature Methods, 2013, 10(10):973-976. doi: 10.1038/nmeth.2600.
[cited by applicant]
Sen et al., “Improved adeno-associated virus (AAV) serotype 1 and 5 vectors for gene therapy,” Scientific Reports, May 2013, 3:1832, DOI:10.1038/srep01832, 1-6.
[cited by applicant]
Sherrington et al., “Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant,” Jul. 1996, 5(7):985-988.
[cited by applicant]
Wang et al., “Rescue and replication of adeno-associated virus type 2 as well as vector DNA sequences from recombinant plasmids containing deletions in the viral inverted terminal repeats: Selective encapsidation of vir…
[cited by applicant]
Wang et al., “Rescue and replication signals of the adeno-associated virus 2 genome,” Journal of Molecular Biology, Jul. 1995, 250(5):573-580.
[cited by applicant]
Xia et al., “Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease,” Neuron, Mar. 2015, 85(5):967-981.
[cited by applicant]
Xiao et al., “Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus,” Journal of Virology, Mar. 1998, 72(3):2224-2232.
[cited by applicant]
Acosta-Baena et al., “Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study,” The Lancet Neurology, Mar. 1, 2011, 10(3):213-20.
[cited by applicant]
Amtul et al., “A presenilin 1 mutation associated with familial frontotemporal dementia inhibits γ-secretase cleavage of APP and notch,” Neurobiology of Disease, Mar. 1, 2002, 9(2):269-73.
[cited by applicant]
Asokan et al., “The AAV vector toolkit: poised at the clinical crossroads,” Molecular Therapy, Apr. 1, 2012, 20(4):699-708.
[cited by applicant]
Ausubel et al., “Current Protocols in Molecular Biology, Sections 9.10-9.14,” Greene Publishing Associates, 1989, 51 pages.
[cited by applicant]
Beglopoulos et al., “Reduced β-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice,” Journal of Biological Chemistry, Nov. 5, 2004, 279(45):46907-14.
[cited by applicant]
Bentahir et al., “Presenilin clinical mutations can affect γ-secretase activity by different mechanisms,” Journal of Neurochemistry, Feb. 2006, 96(3):732-42.
[cited by applicant]
Bessis et al., “Immune responses to gene therapy vectors: influence on vector function and effector mechanisms,” Gene Therapy, Oct. 2004, 11(1):S10-7.
[cited by applicant]
Bose et al., “Role of nucleolin in human parainfluenza virus type 3 infection of human lung epithelial cells,” Journal of Virology, Aug. 1, 2004, 78(15):8146-58.
[cited by applicant]
Brouwers et al., “Molecular genetics of Alzheimer's disease: an update,” Annals of Medicine, Jan. 1, 2008, 40(8):562-83.
[cited by applicant]
Brunkan et al., “Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and γ-secretase activity,” Journal of Neurochemistry, Sep. 2005, 94(5):1315-28.
[cited by applicant]
Chen et al., “Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo,” Proceedings of the National Academy of Sciences, Apr. 12, 1994, 91(8):3054-7.
[cited by applicant]
Chen et al., “Presenilin 1 mutations activate γ42-secretase but reciprocally inhibit ε-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch,” Journal of Biological Chemistry, Sep. 27, 2002, 277…
[cited by applicant]
Cressant et al., “Improved behavior and neuropathology in the mouse model of Sanfilippo type IIIB disease after adeno-associated virus-mediated gene transfer in the striatum,” Journal of Neuroscience, Nov. 10, 2004, 24(…
[cited by applicant]
Crook et al., “A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1,” Nature Medicine, Apr. 1998, 4(4):452-5.
[cited by applicant]
De Jonghe et al., “Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Aβ42 secretion,” Human Molecular Genetics, Aug. 1, 1999, 8(8):1529-40.
[cited by applicant]
De Strooper, “Loss-of-function presenilin mutations in Alzheimer disease: Talking Point on the role of presenilin mutations in Alzheimer disease,” EMBO Reports, Feb. 2007, 8(2):141-6.
[cited by applicant]
Deyle et al., “Adeno-associated virus vector integration,” Current Opinion in Molecular Therapeutics, Aug. 2009, 11(4):442, 11 pages.
[cited by applicant]
Dittgen et al., “Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo,” Proceedings of the National Academy of Sciences, Dec. 28, 2004, 101(52):18206-1…
[cited by applicant]
Doll et al., “Comparison of promoter strengths on gene delivery into mammalian brain cells using AAV vectors,” Gene Therapy, May 1, 1996, 3(5):437-47.
[cited by applicant]
Dong et al., “Poly (d, 1-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs,” Biomaterials, Oct. 1, 2005, 26(30):6068-76.
[cited by applicant]
Duff et al., “Increased amyloid-β42 (43) in brains of mice expressing mutant presenilin 1,” Nature, Oct. 1996, 383(6602):710-3.
[cited by applicant]
EP Extended Search Report in European Appln. No. 19808081.4, dated Feb. 21, 2022, 7 pages.
[cited by applicant]
EP Supplementary European Search Report in European Appln. No. 19808081.4, dated Mar. 11, 2022, 8 pages.
[cited by applicant]
Feng et al., “Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2,” Proceedings of the National Academy of Sciences, May 25, 2004, 101(21):8162-7.
[cited by applicant]
Flotte et al., “Gene expression from adeno-associated virus vectors in airway epithelial cells,” Am J Respir Cell Mol Biol, Sep. 1, 1992, 7(3):349-56.
[cited by applicant]
Foley et al., “Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption,” Journal of Controlled Release, Dec. 28, 2014, 196:71-8.
[cited by applicant]
GenBank Accession No. NP 000438.2, “presenilin-2 isoform 1 [
[cited by applicant]
Gholizadeh et al., “Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice,” Neuropsychopharmacology, Dec. 2014, 39(13):3100-11.
[cited by applicant]
Gonçalves et al., “Adeno-associated virus: from defective virus to effective vector,” Virology Journal, Dec. 2005, 2(1):1-7.
[cited by applicant]
Haberman et al., “Inducible long-term gene expression in brain with adeno-associated virus gene transfer,” Gene Therapy, Dec. 1998, 5(12):1604-11.
[cited by applicant]
Handler et al., “Presenilin-1 regulates neuronal differentiation during neurogenesis,” Development, Jun. 15, 2000, 127(12):2593-606.
[cited by applicant]
Heilig et al., “A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of γ-secretase activity,” Journal of Biological Chemistry, Jul. 16, 2010, 285(29):2…
[cited by applicant]
Heilig et al., “Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production,” Journal of Neuroscience, Jul. 10, 2013, 33(28):11606-17.
[cited by applicant]
Henikoff et al., “Amino acid substitution matrices from protein blocks,” Proceedings of the National Academy of Sciences, Nov. 15, 1992, 89(22):10915-9.
[cited by applicant]
Hermonat et al., “Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells,” Proceedings of the National Academy of Sciences, Oct. 1, 1984,…
[cited by applicant]
Herreman et al., “γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation,” Journal of Cell Science, Mar. 15, 2003, 116(6):1127-36.
[cited by applicant]
Herskowitz, “Functional inactivation of genes by dominant negative mutations,” Nature, Sep. 1987, 329(6136):219-22.
[cited by applicant]
Hester et al., “AAV as a gene transfer vector for the treatment of neurological disorders: novel treatment thoughts for ALS,” Current Gene Therapy, Oct. 1, 2009, 9(5):428-33.
[cited by applicant]
Hiltunen et al., “Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombin…
[cited by applicant]
Hitoshi Niwa et al., “Efficient selection for high-expression transfectants with a novel eukaryotic vector,” Gene, Dec. 15, 1991, 108(2):193-9.
[cited by applicant]
Hsu et al., “Discovery and validation of autosomal dominant Alzheimer's disease mutations,” Alzheimer's Research & Therapy, Dec. 2018, 10(1):1-8.
[cited by applicant]
Iwata et al., “Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice,” Scientific Reports, Mar. 18, 2013, 3(1):1-8.
[cited by applicant]
Jackson et al., “AAV9 supports wide-scale transduction of the CNS and TDP-43 disease modeling in adult rats,” Molecular Therapy—Methods & Clinical Development, Jan. 1, 2015, 2:15036, 8 pages.
[cited by applicant]
Kang et al., “An evolutionarily conserved role of presenilin in neuronal protection in the aging
[cited by applicant]
Kelleher et al., “Presenilin-1 mutations and Alzheimer's disease,” Proceedings of the National Academy of Sciences, Jan. 24, 2017, 114(4):629-31.
[cited by applicant]
Kim et al., “Presenilins are required for maintenance of neural stem cells in the developing brain,” Molecular Neurodegeneration, Dec. 2008, 3(1):1-3.
[cited by applicant]
Kim et al., “Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo,” European Journal of Neuroscience, Apr. 2013, 37(8):1203-20.
[cited by applicant]
Klein et al., “Dose and promoter effects of adeno-associated viral vector for green fluorescent protein expression in the rat brain,” Experimental Neurology, Jul. 1, 2002, 176(1):66-74.
[cited by applicant]
Kosik et al., “Homozygosity of the autosomal dominant Alzheimer disease presenilin 1 E280A mutation,” Neurology, Jan. 13, 2015, 84(2):206-8.
[cited by applicant]
Kumar-Singh et al., “Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40,” Human Mutation, Jul. 2006, 27(7):686-95.
[cited by applicant]
Lalli et al., “Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease,” Alzheimer's & Dementia, Oct. 2014, 10:S277-83.
[cited by applicant]
Langer et al., “New methods of drug delivery,” Science, Sep. 28, 1990, 249(4976):1527-33.
[cited by applicant]
Lebkowski et al., “Adeno-associated virus: a vector system for efficient introduction and integration of DNA into a variety of mammalian cell types,”. Molecular and Cellular Biology, Oct. 1, 1988, 8(10):3988-96.
[cited by applicant]
Lee et al., “Presenilins regulate synaptic plasticity and mitochondrial calcium homeostasis in the hippocampal mossy fiber pathway,” Molecular Neurodegeneration, Dec. 2017, 12(1):1-5.
[cited by applicant]
Lee et al., “Synaptic function of nicastrin in hippocampal neurons,” Proceedings of the National Academy of Sciences, Jun. 17, 2014, 111(24):8973-8.
[cited by applicant]
Lei et al., “Structure-function analysis of human glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a,” Journal of Biological Chemistry, May 19, 1995, 270(20):11882-6.
[cited by applicant]
Lemere et al., “The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology,” Nature Medicine, Oct. 1996, 2(10):1146-50.
[cited by applicant]
Levitan et al., “Assessment of normal and mutant human presenilin function in Caenorhabditis elegans,” Proceedings of the National Academy of Sciences, Dec. 10, 1996, 93(25):14940-4.
[cited by applicant]
Levy-Lahad et al., “Candidate gene for the chromosome 1 familial Alzheimer's disease locus,” Science, Aug. 18, 1995, 269(5226):973-7.
[cited by applicant]
Liu et al., “Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector,” Scientific Reports, May 19, 2017, 7(1):1-9.
[cited by applicant]
Löbenberg et al., “Improved body distribution of 14C-labelled AZT bound to nanoparticles in rats determined by radioluminography,” Journal of Drug Targeting, Jan. 1, 1998. 5(3):171-9.
[cited by applicant]
Lopera et al., “Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation,” Jama, Mar. 12, 1997, 277(10):793-9.
[cited by applicant]
Marambaud et al., “A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions,” The EMBO Journal, Apr. 15, 2002, 21(8):1948-56.
[cited by applicant]
Mauro et al., “A critical analysis of codon optimization in human therapeutics,” Trends in Molecular Medicine, Nov. 1, 2014, 20(11):604-13.
[cited by applicant]
Mayford et al., “Control of memory formation through regulated expression of a CaMKII transgene,” Science, Dec. 6, 1996, 274(5293):1678-83.
[cited by applicant]
McLaughlin et al., “Adeno-associated virus general transduction vectors: analysis of proviral structures,” Journal of Virology, Jun. 1, 1988, 62(6):1963-73.
[cited by applicant]
McLean et al., “Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection,” Neuroscience Letters, Jul. 25, 2014, 576:73-8.
[cited by applicant]
Mingozzi et al., “Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges,” Nature Reviews Genetics, May 2011, 12(5):341-55.
[cited by applicant]
Moehlmann et al., “Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production,” Proceedings of the National Academy of S…
[cited by applicant]
Mucke et al., “High-level neuronal expression of Aβ1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation,” Journal of Neuroscience, Jun. 1, 2000, 20(11):4050-8.
[cited by applicant]
Muzyczka, “Use of adeno-associated virus as a general transduction vector for mammalian cells,” Viral Expression Vectors, 1992, vol. 1992:97-129.
[cited by applicant]
Palmisano et al., “Characterization of membrane-shed microvesicles from cytokine-stimulated β-cells using proteomics strategies,” Molecular & Cellular Proteomics, Aug. 1, 2012, 11(8):230-43.
[cited by applicant]
Parra et al., “Memory binding and white matter integrity in familial Alzheimer's disease, ” Brain, May 1, 2015, 138(5):1355-69.
[cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2019/033616, dated Nov. 24, 2020, 12 pages.
[cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2020/034040, dated Nov. 16, 2021, 7 pages.
[cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2019/033616, dated Oct. 28, 2019, 18 pages.
[cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2020/034040, dated Sep. 17, 2020, 10 pages.
[cited by applicant]
Podlisny et al., “Presenilin proteins undergo heterogeneous endoproteolysis between Thr291and Ala299and occur as stable N-and C-terminal fragments in normal and Alzheimer brain tissue,” Neurobiology of Disease, Jan. 1, …
[cited by applicant]
Qi et al., “Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid β-protein 42 in Chinese hamster ovary cells,” Biochemistry, Feb. 4, 2003, 42(4):1042-52.
[cited by applicant]
Qian et al., “Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression,” Neuron, Mar. 1, 1998, 20(3):611-7.
[cited by applicant]
Reiman et al., “Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study,” The Lancet Neurology, Dec. …
[cited by applicant]
Rios-Romenets et al., “The value of pre-screening in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease trial,” The Journal of Prevention of Alzheimer's Disease, Jan. 2018, 5(1):49-54.
[cited by applicant]
Robinson et al., “Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis,” Molecular Therapy, Aug. 1, 2018, 26(8):2034-46.
[cited by applicant]
Rogaev et al., “Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene,” Nature, Aug. 1995, 376(6543):775-8.
[cited by applicant]
Ryan et al., “Correlating familial Alzheimer's disease gene mutations with clinical phenotype,” Biomarkers in Medicine, Feb. 2010, 4(1):99-112.
[cited by applicant]
Ryman et al., “Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis,” Neurology, Jul. 15, 2014, 83(3):253-60.
[cited by applicant]
Saito et al., “Potent amyloidogenicity and pathogenicity of Aβ43,” Nature Neuroscience, Aug. 2011, 14(8):1023-32.
[cited by applicant]
Sakuma et al., “Mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal tract,” International Journal of Pharmaceutics, Jan. 25, 1999, 177(2):161-72.
[cited by applicant]
Samulski et al., “Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression,” Journal of Virology, Sep. 1, 1989, 63(9):3822-8.
[cited by applicant]
Saura et al., “Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice,” Journal of N…
[cited by applicant]
Saura et al., “Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration,” Neuron, Apr. 8, 2004, 42(1):23-36.
[cited by applicant]
Schroeter et al., “A presenilin dimer at the core of the γ-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis,” Proceedings of the National Academy of Sciences, Oct. 28, 2003, 100(22):13075…
[cited by applicant]
Sepulveda-Falla et al., “Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer's disease,” Brain Pathology, Jul. 2011, 21(4):452-63.
[cited by applicant]
Sepulveda-Falla et al., “Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis,” The Journal of Clinical Investigation, Apr. 1, 2014, 124(4):1552-67.
[cited by applicant]
Shen et al., “Skeletal and CNS defects in Presenilin-1-deficient mice,” Cell, May 16, 1997, 89(4):629-39.
[cited by applicant]
Shen et al., “The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism,” Proceedings of the National Academy of Sciences, Jan. 9, 2007, 104(2):403-9.
[cited by applicant]
Sherrington et al., “Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease,” Nature, Jun. 1995, 375(6534):754-60.
[cited by applicant]
Siman et al., “Presenilin-1 P264L knock-in mutation: differential effects on Aβ production, amyloid deposition, and neuronal vulnerability,” Journal of Neuroscience, Dec. 1, 2000, 20(23):8717-26.
[cited by applicant]
Song et al., “Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations,” Proceedings of the National Academy of Sciences, Jun. 8, 1999, 96(12…
[cited by applicant]
Steiner et al., “A pathogenic presenilin-1 deletion causes aberrant Aβ42 production in the absence of congophilic amyloid plaques,” Journal of Biological Chemistry, Mar. 9, 2001, 276(10):7233-9.
[cited by applicant]
Sun et al., “Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase,” Proceedings of the National Academy of Sciences, Jan. 24, 2017, 114(4):E476-85.
[cited by applicant]
Sun et al., “Hippocampal spatial memory impairments caused by the familial Alzheimer's disease-linked presenilin 1 M146V mutation,” Neurodegenerative Diseases, Aug. 2005, 2(1):6-15.
[cited by applicant]
Szymczak et al., “Correction of multi-gene deficiency in vivo using a single‘self-cleaving’2A peptide-based retroviral vector,” Nature Biotechnology, May 2004, 22(5):589-94.
[cited by applicant]
Tabuchi et al., “Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration,” Journal of Neuroscience, Jun. 3, 2009, 29(22):7290-301.
[cited by applicant]
Théry et al., “Isolation and characterization of exosomes from cell culture supernatants and biological fluids,” Current Protocols in Cell Biology, Mar. 2006, 30(1):3-22.
[cited by applicant]
Trichas et al., “Use of the viral 2A peptide for bicistronic expression in transgenic mice,” BMC Biology, Dec. 2008, 6(1):1-3.
[cited by applicant]
Tysoe et al., “A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease,” The American Journal of Human Genetics, Jan. 1, 1998, 62(1):70-6.
[cited by applicant]
Virovic et al., “Novel delivery methods for treatment of viral hepatitis: an update,” Expert Opinion on Drug Delivery, Jul. 1, 2005, 2(4):707-17.
[cited by applicant]
Waldenström et al., “Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells,” PloS one, Apr. 10, 2012, 7(4):e34653, 7 pages.
[cited by applicant]
Walker et al., “Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios,” Journal of Neurochemistry, Jan. 2005, 92(2):294-301.
[cited by applicant]
Watanabe et al., “Dominant negative mechanism of Presenilin-1 mutations in FAD,” Proceedings of the National Academy of Sciences, Nov. 28, 2017, 114(48):12635-7.
[cited by applicant]
Watanabe et al., “Familial frontotemporal dementia-associated presenilin-1 c. 548G> T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice,” Journal of Neuroscience, Apr. 11, 2012, …
[cited by applicant]
Watanabe et al., “Indirect regulation of presenilins in CREB-mediated transcription,” Journal of Biological Chemistry, May 15, 2009, 284(20):13705-13.
[cited by applicant]
Watanabe et al., “Partial loss of presenilin impairs age-dependent neuronal survival in the cerebral cortex,” Journal of Neuroscience, Nov. 26, 2014, 34(48):15912-22.
[cited by applicant]
Wiley et al., “Familial Alzheimer's disease mutations inhibit γ-secretase-mediated liberation of β-amyloid precursor protein carboxy-terminal fragment,” Journal of Neurochemistry, Sep. 2005, 94(5):1189-201.
[cited by applicant]
Wines-Samuelson et al., “Characterization of age-dependent and progressive cortical neuronal degeneration in presenilin conditional mutant mice,” PLoS One, Apr. 15, 2010, 5(4):e10195.
[cited by applicant]
Wines-Samuelson et al., “Presenilins in the developing, adult, and aging cerebral cortex,” The Neuroscientist, Oct. 2005, 11(5):441-51.
[cited by applicant]
Wines-Samuelson et al., “Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons,” Developmental Biology, Jan. 15, 2005, 277(2):332-46.
[cited by applicant]
Wu et al., “Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons,” Proceedings of the National Academy of Sciences, Sep. 10, 2013, 110(37):15091-6.
[cited by applicant]
Xia et al., “Loss of Aβ43 production caused by presenilin-1 mutations in the knockin mouse brain,” Neuron, Apr. 20, 2016, 90(2):417-22.
[cited by applicant]
Xia et al., “Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease,” Neuron, Mar. 4, 2015, 85(5):967-81.
[cited by applicant]
Xia, “Relationship between presenilinase and gamma-secretase,” Drug News & Perspectives, Mar. 1, 2003, 16(2):69-74.
[cited by applicant]
Yu et al., “APP processing and synaptic plasticity in presenilin-1 conditional knockout mice,” Neuron, Sep. 13, 2001, 31(5):713-26.
[cited by applicant]
Zhang et al., “Inactivation of presenilins causes pre-synaptic impairment prior to post-synaptic dysfunction,” Journal of Neurochemistry, Dec. 2010, 115(5):1215-21.
[cited by applicant]
Zhang et al., “Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased Aβ42 secretion in mammalian cells but impaired Notch/lin-I2 signalling in C. elegans,” Neuroreport, Sep. 28, 20…
[cited by applicant]
Zhang et al., “Presenilins are essential for regulating neurotransmitter release,” Nature, Jul. 2009, 460(7255):632-6.
[cited by applicant]
Zhao et al., “Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies,” Journal of Biological Chemistry, Nov. 3, 2017, 292(44):18325-43.
[cited by applicant]
Zhou et al., “Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization,” Proceedings of the National Academy of Sciences, Nov. 28, 2017, 114(48):12731-6.
[cited by applicant]
Zimmermann et al., “Electrolyte-and pH-stabilities of aqueous solid lipid nanoparticle (SLN™) dispersions in artificial gastrointestinal media,” European Journal of Pharmaceutics and Biopharmaceutics, Sep. 1, 2001, 52(2…
[cited by applicant]
EP Extended Search Report in European Appln. No. 20813435.3. dated Jun. 12, 2023, 6 pages.
[cited by applicant]
GenBank Accession No. AAW01891, “Sequence 12 from U.S. Pat. No. 6,783,955,” dated Dec. 14, 2004, 1 page.
[cited by applicant]
GenBank Accession No. AFD46703, “Sequence 2 from U.S. Pat. No. 8,129,334,” Mar. 14, 2012, 1 page.
[cited by applicant]
AU Office Action in Australian Appln. No. 2019272848, mailed on Oct. 29, 2024, 5 pages.
[cited by applicant]
CN Office Action in Chinese Appln. No. 201980049127.3, mailed on Dec. 18, 2024, 16 pages (with English translation).
[cited by applicant]
CN Office Action in Chinese Appln. No. 202080052274.9, mailed on Sep. 26, 2024, 7 pages (with English translation).
[cited by applicant]
Bäck et al., “Neuronal activation stimulates cytomegalovirus promoter-driven transgene expression,” Molecular Therapy Methods & Clinical Development, Sep. 2019, 14:180, 13 pages.
[cited by applicant]
CA Office Action in Canadian Appln. No. 3,100,946, mailed on Feb. 5, 2025, 5 pages.
[cited by applicant]
Emery, “The use of chromatin insulators to improve the expression and safety of integrating gene transfer vectors,” Human Gene Therapy, Jun. 2011, 22(6):761-74.
[cited by applicant]
JP Office Action in Japanese Appln. No. 2021-569550, mailed on Jan. 14, 2025, 3 pages (with English translation).
[cited by applicant]
Kim et al., “Human P-Globin Second Intron Highly Enhances Expression of Foreign Genes from Murine Cytomegalovirus Immediate-Early Promoter,” Journal of Microbiology and Biotechnology, Jan. 2005, 15(3):544-50.
[cited by applicant]
Kou et al., “Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications,” Molecular Neurobiology, Feb. 2015, 51:43, 29 pages.
[cited by applicant]
Leppek et al., “Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them,” Nature Reviews Molecular Cell Biology, Mar. 2018, 19(3):158, 36 pages.
[cited by applicant]
Naso et al., “Adeno-associated virus (AAV) as a vector for gene therapy,” BioDrugs, Aug. 2017, 31(4):317-34.
[cited by applicant]
Ólafsdóttir et al., “In vitro analysis of expression vectors for DNA vaccination of horses: the effect of a Kozak sequence,” Acta Veterinaria Scandinavica, Dec. 2008, 50:1-7.
[cited by applicant]
Pesole et al., “UTRdb and UTRsite: specialized databases of sequences and functional elements of 5′ and 3′ untranslated regions of eukaryotic mRNAs, Update 2002.” Nucleic Acids Research, Jan. 2002, 30(1):335-40.
[cited by applicant]
Borel et al., “Recombinant AAV as a platform for translating the therapeutic potential of RNA interference,” Molecular Therapy, Apr. 2014, 22(4):692-701.
[cited by applicant]
Kilikevicius et al., “Reexamining assumptions about miRNA-guided gene silencing,” Nucleic Acids Research, Jan. 2022, 50(2):617-34.
[cited by applicant]
O'Reilly et al., “RNA interference-mediated suppression and replacement of human rhodopsin in vivo,” The American Journal of Human Genetics, Jul. 2007, 81(1): 127-35.
[cited by applicant]
Riolo et al., “miRNA targets: from prediction tools to experimental validation,” Methods and Protocols, Dec. 2020, 4(1):1, 20 pages.
[cited by applicant]
Seok et al., “MicroRNA target recognition: insights from transcriptome-wide non-canonical interactions,” Molecules and Cells, May 2016, 39(5):375-81.
[cited by applicant]
SG Office Action in Singaporean Appln. No. 11202205560S, mailed on Jun. 5, 2025, 12 pages.
[cited by applicant]