Granted Patent
B2
US 12,311,034 · App. 17/271,432 · Granted May 27, 2025
Feedback enabled synthetic genes, target seed match cassettes, and their uses
View Patent ↗
Loading inventors, assignments & file history…
Abstract
This invention relates to feedback-enabled synthetic genes, polynucleotide target cassettes, vectors, and pharmaceutical compositions for the purpose of providing transgene expression in target tissues that is capable of endogenous regulation for treating disorders such as dose-sensitive intellectual ability disorders, as well as methods of making and methods of using the same.
Claims (10)
1. A synthetic gene comprising:
a polynucleotide comprising a coding region encoding MECP2 and one or more regulatory regions, wherein the one or more regulatory regions comprise the nucleotide sequence of SEQ ID NO:2.
2. A vector comprising the synthetic gene of claim 1 .
3. The vector of claim 2 , wherein the vector is a viral vector.
4. The vector of claim 2 , wherein the vector is an adeno-associated virus (AAV) vector.
5. The vector of claim 4 , wherein the AAV vector is an AAV9 vector.
6. A pharmaceutical composition comprising the synthetic gene of claim 1 and a pharmaceutically acceptable carrier.
7. A method of delivering a synthetic gene to a subject, the method comprising administering to the subject the synthetic gene of claim 1 , thereby delivering the synthetic gene to the subject.
8. A polynucleotide target cassette for providing dose dependent inhibitory feedback to a synthetic gene, the cassette comprising a regulatory region comprising the sequence of SEQ ID NO:2.
9. A method of preparing a synthetic gene comprising a polynucleotide comprising a coding region encoding MECP2 and one or more regulatory regions, comprising the step of inserting the polynucleotide target cassette of claim 8 into a regulatory region of the synthetic gene.
Assignments (4)
RELEASE OF SECURITY INTEREST
Recorded Feb 13, 2026
From: TRINITY CAPITAL INC.
To: TAYSHA GENE THERAPIES, INC.
Reel/Frame 074858/0456 →
SECURITY INTEREST
Recorded Aug 8, 2025
From: TAYSHA GENE THERAPIES, INC.
To: TRINITY CAPITAL, INC., AS ADMINISTRATIVE AGENT AND COLLATERAL AGENT
Reel/Frame 071976/0658 →
SECURITY INTEREST
Recorded Jul 30, 2025
From: TAYSHA GENE THERAPIES, INC.
To: TRINITY CAPITAL INC.
Reel/Frame 071886/0097 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 16, 2021
From: GRAY, STEVEN JAMES; SINNETT, SARAH
To: THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
Reel/Frame 055604/0487 →
Continuity (3)
Provisional Application
62861044
· Jun 13, 2019
Provisional Application
62725126
· Aug 30, 2018
References Cited (81)
US 4501729A
· Boucher et al.
· 1985
[cited by applicant]
US 5399346A
· Anderson et al.
· 1995
[cited by applicant]
US 7195916B2
· Qin et al.
· 2007
[cited by applicant]
US 7201898B2
· Monahan et al.
· 2007
[cited by applicant]
US 8440431B2
· Voytas et al.
· 2013
[cited by applicant]
US 8871445B2
· Cong et al.
· 2014
[cited by applicant]
US 8889356B2
· Zhang
· 2014
[cited by applicant]
US 20140200261A1
· Hoge
· 2014
[cited by examiner]
JP 2016504050A
· 2016
[cited by applicant]
WO 0191803A2
· 2001
[cited by applicant]
WO 2009126563A1
· 2009
[cited by applicant]
WO 2018172795A1
· 2018
[cited by applicant]
Sinnett et al., Jun. 16, 2017, “Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery” Molecular Therapy Methods & Clinical Development, 5, p. 106-11…
[cited by examiner]
Gadalla et al., 2013, “Improved Survival and Reduced Phenotypic Severity Following AAV9/MECP2 Gene Transfer to Neonatal and Juvenile Male Mecp2 Knockout Mice” Molecular Therapy, 21(1), p. 18-30 (Year: 2013).
[cited by examiner]
Guy et al., 2001, “A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome” Nature Genetics, 27, p. 322-326 (Year: 2001).
[cited by examiner]
Sinnett, Boyle, et al., 2021, “Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice” Brain, 144, p. 3005-3019 (Year: 2021).
[cited by examiner]
Iqbal and Iqbal, 2014, “Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications”, Molecular Biology International, p. 1-9 (Year: 2014).
[cited by examiner]
Tabrizi et al., 2019, “Huntingtin Lowering Strategies for Disease Modification in Huntington's Disease”, Neuron Review, p. 801-819 (Year: 2019).
[cited by examiner]
Chipman and Pasquinelli, 2019, “miRNA Targeting: Growing beyond the Seed”, Trends in Genetics, 35(3), p. 215-255 (Year: 2019).
[cited by examiner]
Sætrom et al., 2007, “Distance constraints between microRNA target sites dictate efficacy and cooperativity” Nucleic Acids Research, 35(7), p. 2333-2342 (Year: 2007).
[cited by examiner]
Agarwal et al., 2015, “Predicting effective microRNA target sites in mammalian mRNAs” eLIFE, 4:e05005 (Year: 2015).
[cited by examiner]
Extended European Search Report corresponding to European Patent Application No. 19853521.3 (8 pages) (dated May 19, 2022).
[cited by applicant]
Gadalla et al. “Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome” Molecular Therapy: Methods & Clinical Development, Supplemental Information,…
[cited by applicant]
Sinnett et al. “Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice” Bain, 144:3005-3019 (2021).
[cited by applicant]
Zuo et al. “Specific Expression of MicroRNA in Different Tissues of Nervous System and Expression Changes in Nerve Regeneration” Sheng Li Ke Xue Jin Zhan, 42(4):261-268 (2011) (English translation of abstract).
[cited by applicant]
International Preliminary Report on Patentability corresponding to International Application No. PCT/US2019/048776, dated Mar. 11, 2021, 10 pages.
[cited by applicant]
Agarwal et al. “Predicting effective microRNA target sites in mammalian mRNAs” eLife, 4:e05005 (2015).
[cited by applicant]
Araujo et al. “Cerebal overinhibition could be the basis for the high prevalence of epilepsy in persons with Down syndrome” Epilepsy & Behavior, 53:120-125 (2015) (Abstract only).
[cited by applicant]
Berube et al. “Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice” Human Molecular Genetics, 11(3):253-261 (2002).
[cited by applicant]
Boettcher et al. “Choosing the Right Tool for the Job: RNAi, TALEN, or CRISPR” Molecular Cell, 58:575-585 (2015).
[cited by applicant]
Bouazzi et al. “Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe Intellectual deficiency without alpha thalassaemia” Indian Journal of Medical Research, 143:43-48 (2016).
[cited by applicant]
Carter et al. “Neuroanatomic correlates of autism and stereotypy in children with Down syndrome” NeuroReport, 19(6):653-656 (2008) (Abstract only).
[cited by applicant]
Cesaretti et al. “Prenatal detection of 5q14.3 duplication including MEF2C and brain phenotype” American Journal of Medical Genetics, 170A(5):1352-1357 (2016) (Abstract only).
[cited by applicant]
Copping et al. “Neuronal overexpression of Ube3a isoform 2 causes behavioral impairments and neuroanatomical pathology relevant to 15q11.2-q13.3 duplication syndrome” Human Molecular Genetics, 26(20):3995-4010 (2017).
[cited by applicant]
De Queiroz et al. “Orofacial Findings and Dental Treatment in an 8-year-old Patient With Trisomy 18: A Case Report” Journal of Dentistry for Children, 74:67-72 (2007).
[cited by applicant]
De Winter et al. “Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system” Orphanet Journal of Rare Diseases, 11(37):1-12 (2016).
[cited by applicant]
Duchon et al. “DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome” Frontiers in Behavioral Neuroscience, 10(104):1-17 (2016).
[cited by applicant]
Fuertes-Gonzalez et al. “Oral findings in Rett syndrome: A systematic review of the dental literature” Med Oral Patol Oral Cir Bucal, 16(1):e37-41 (2011).
[cited by applicant]
Gadalla et al. “Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome” Molecular Therapy: Methods & Clinical Development, 5:180-190 (2017).
[cited by applicant]
Grimson et al. “MicroRNA Targeting Specificity in Mammals: Determinants beyond Seed Pairing” Molecular Cell, 27:91-105 (2007).
[cited by applicant]
Guedj et al. “DYRK1A: a master regulatory protein controlling brain growth” Neurobiology of Disease, 46(1):190-203 (2012) (Abstract only).
[cited by applicant]
Hassan et al. “miR-218 Directs a Wnt Signaling Circuit to Promote Differentiation of Osteoblasts and Osteomimicry of Metastatic Cancer Cells” Journal of Biological Chemistry, 287(50):42084-42092 (2012).
[cited by applicant]
Hegarty et al. “Zeb2: A multifunctional regulator of nervous system development” Progress in Neurobiology, 132:81-95 (2015) (Abstract only).
[cited by applicant]
Kalsotra et al. “The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue dramatically altering miRNA and mRNA expression” Cell Reports, 6(2):336-345 (2014).
[cited by applicant]
Kent et al. “Speech Impairment in Down Syndrome: A Review” Journal of Speech, Language, and Hearing Research, 56(1):178-210 (2013).
[cited by applicant]
Leonard et al. “Clinical and biological progress over 50 years in Rett syndrome” Nature Reviews Neurology, 13:37-51 (2017).
[cited by applicant]
Lewis et al. “Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets” Cell, 120:15-20 (2005).
[cited by applicant]
Luco et al. “Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature” BMC Medical Genetics, 17(15):1-8 (2016).
[cited by applicant]
Lugtenberg et al. “Xq13.2q21.1 duplication encompassing the ATRX gene in a man with mental retardation, minor facial and genital anomalies, short stature and broad thorax” American Journal of Medical Genetics, 149A(4):7…
[cited by applicant]
Matsumoto et al. “An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities” Journal of Human Genetics, 58:755-757 (2013).
[cited by applicant]
Miguet et al. “Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features” Journal of Medical Genetics, 55:359-371 (201…
[cited by applicant]
Miyata et al. “Periventricular small cystic lesions in a patient with Coffin-Lowry syndrome who exhibited a novel mutation in the RPS6KA3 gene” Brain and Development, 40(7):566-569 (2018) (Abstract only).
[cited by applicant]
Morino et al. “Eight years of follow-up after laminectomy of calcium pyrophosphate crystal deposition in the cervical yellow ligament of patient with Coffin-Lowry syndrome” Medicine, 95(31):e4468 (2016).
[cited by applicant]
Mullegama et al. “Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder” European Journal of Human Genetics, 22:57-63 (2014).
[cited by applicant]
Pelc et al. “Behavior and neuropsychiatric manifestations in Angelman syndrome” Neuropsychiatric Disease and Treatment. 4(3):577-584 (2008).
[cited by applicant]
Pelc et al. “Are there distinctive sleep problems in Angelman syndrome?” Sleep Medicine, 9(4):434-441 (2008) (Abstract only).
[cited by applicant]
Roberts et al. “Anatomy of trisomy 18” Clinical Anatomy, 29(5):628-632 (2016) (Abstract only).
[cited by applicant]
Rosenfeld et al. “Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly” Molecular Syndromology, 3:247-254 (2012).
[cited by applicant]
Schirle et al. “Structural Basis for microRNA Targeting” Science, 346(6209):608-613 (2014).
[cited by applicant]
Schirle et al. “Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets” eLife, 4:e07646 (2015).
[cited by applicant]
Seltzer et al. “Genetic disorders associated with postnatal microcephaly” American Journal of Medical Genetics Part C, Seminars in Medical Genetics, 166C(2):140-155 (2014) (Abstract only).
[cited by applicant]
Sinnett et al. “Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery” Molecular Therapy: Methods & Clinical Development, 5:106-115 (2017).
[cited by applicant]
Talkowski et al. “Assessment of 2q23.1 Microdeletion Syndrome Implicates MBD5 as a Single Causal Locus of Intellectual Disability, Epilepsy, and Autism Spectrum Disorder” American Journal of Human Genetics, 89:551-563 (…
[cited by applicant]
Tejada et al. “A Child With Mild X-Linked Intellectual Disability and a Microduplication at Xp22.12 Including RPS6KA3” 128:e1029-e1033 (2011).
[cited by applicant]
Tillotson et al. “Radically truncated MeCP2 rescues Rett syndrome-like neurological defects” Nature, 550(7676):398-401 (2017).
[cited by applicant]
Tos et al. “A familial case of Coffin-Lowry syndrome caused by RPS6KA3 C.898C>T mutation associated with multiple abnormal brain imaging findings” Genetic Counseling, 26(1):47-52 (2015) (Abstract only).
[cited by applicant]
Touraine et al. “A syndromic form of X-linked mental retardation: the Coffin-Lowry syndrome” European Journal of Pediatrics, 161:179-187 (2002).
[cited by applicant]
Urdinguio et al. “Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome” Epigenetics, 5(7):656-663 (2010).
[cited by applicant]
Vrecar et al. “Further Clinical Delineation of the MEF2C Haploinsufficiency Syndrome” Journal of Pediatric Genetics, 6:129-141 (2017).
[cited by applicant]
Wegiel et al. “Differences Between the Pattern of Developmental Abnormalities in Autism Associated With Duplications 15q11.2-q13 and Idiopathic Autism” Journal of Neuropathology & Experimental Neurology, 71(5):382-397 (…
[cited by applicant]
Wu et al. “Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome” Proceedings of the National Academy of Sciences USA, 107(42):18161-18166 (2010).
[cited by applicant]
Yuan et al. “A de novo triplication on 2q22.3 including the entire ZEB2 gene associated with global developmental delay, multiple congenital anomalies and behavioral abnormalities” Molecular Cytogenetics, 8(99):1-7 (201…
[cited by applicant]
Gadalla K.K.E. et al. “Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome” Molecular Therapy: Methods & Clinical Development, 5:180-190 2017.
[cited by applicant]
Gadalla, K. K. E. et al., “Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice”, Molecular Therapy, 21(1):18-30 2013.
[cited by applicant]
International Search Report and Written Opinion corresponding to International Application No. PCT/US2019/048776, dated Dec. 17, 2019 14 pages.
[cited by applicant]
McGowan H et al. “Regulatory functions and pathological relevance of the MECP2 3′ UTR in the central nervous system” Cell Regeneration, 4(1):1-10 2015.
[cited by applicant]
Sinnett S.E. et al. “Improved MECP2 gene therapy extends the survival of MeCP2-null mice without apparent toxicity after intracisternal delivery” Molecular Therapy: Methods & Clinical Development, 5:106-115 2017.
[cited by applicant]
Muniategui et al. “Joint analysis of miRNA and mRNA expression data” Briefings in Bioinformatics, 14(3):263-278 (2013).
[cited by applicant]