IP Library › Granted Patent US 12,516,376
Granted Patent B2
US 12,516,376 · App. 16/973,353 · Granted Jan 6, 2026

Optimizing BAG3 gene therapy

Inventor: Arthur M. Feldman (Wynnewood, PA)
Assignee: TEMPLE UNIVERSITY—OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
C12Q1/6883A61K48/005C12Q2600/118C12Q2600/156
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Quick Facts
Patent No.
US 12,516,376
App. No.
16/973,353
Granted
Jan 6, 2026
Kind
B2
Abstract

Identification of BAG3 (Bcl2-associated anthanogene 3) genetic variants were associated with the prevalence non-ischemic or ischemic dilated cardiomyopathy (DCM) and DCM outcomes in individuals of African ancestry.

Claims (15)

1 . A method of diagnosing and treating a patient having cardiac disease, comprising: identifying in a patient sample, at least one Bcl2-associated anthanogene 3 (BAG3) genetic variant as compared to a control BAG3 nucleic acid sequence, wherein the BAG 3 genetic variant comprises a 3 nucleotide insertion that adds an alanine at position 160 (p.Ala160dup, 10:121429647 A/AGCG; rs139438727) or a single nucleotide variant (SNV) in-frame insertion comprising: p.Pro63Ala (10:121429369 C/G; rs133031999); p.His83Gln (10:151331972; rs151331972); Ala479Val (10:121436502 C/T; rs34656239) or combinations thereof, wherein detection of the BAG 3 genetic variant is predictive of whether an increase in BAG3 levels is therapeutic for the patient, and, administering to the patient identified as having such a genetic variant, a therapeutically effective amount of a BAG3 protein or biologically active fragment thereof or expression vector for expression of a BAG3 protein or biologically active fragment thereof.

2 . The method of claim 1 , wherein the 3 nucleotide insertion adds an alanine at position 160 (p.Ala160dup, 10:121429647 A/AGCG; rs139438727).

3 . The method of claim 1 , wherein the genetic variant comprises: p.Pro63Ala (10:121429369 C/G; rs133031999); p.His83Gln (10:151331972; rs151331972); Ala479Val (10:121436502 C/T; rs34656239) or combinations thereof.

4 . The method of claim 1 , wherein the expression vector comprises a viral vector, cardiotropic vector, plasmid, or a yeast vector.

5 . The method of claim 4 , wherein the cardiotropic vector comprises an adenovirus vector, an adeno-associated virus vector (AAV), a coxsackie virus vector, cytomegalovirus vector, Epstein-Barr virus vector, parvovirus vector, or hepatitis virus vectors.

6 . The method of claim 5 , wherein the expression vector is a cardiotropic pseudotyped viral vector.

7 . The method of claim 1 , wherein the cardiac disease is heart failure.

8 . The method of claim 1 , wherein the BAG3 polypeptide or fragment thereof is linked to another polypeptide.

9 . A method of treating a patient having cardiac disease, wherein said patient has at least one Bcl2-associated anthanogene 3 (BAG3) nucleotide variant (NV) in-frame insertion as compared to a control BAG3 nucleic acid sequence, wherein the nucleotide variant comprises a 3 nucleotide insertion that adds an alanine at position 160 (p.Ala160dup, 10:121429647 A/AGCG; rs139438727) or a single nucleotide variant (SNV) in-frame insertion comprising: p.Pro63Ala (10:121429369 C/G; rs133031999); p.His83Gln (10:151331972; rs151331972); Ala479Val (10:121436502 C/T; rs34656239) or combinations thereof, comprising administering to said patient a therapeutically effective amount of a BAG3 protein or biologically active fragment thereof or expression vector for expression of a BAG3 protein or biologically active fragment thereof.

10 . The method of claim 9 , wherein the 3 nucleotide insertion adds an alanine at position 160 (p.Ala160dup, 10:121429647 A/AGCG; rs139438727).

11 . The method of claim 9 , wherein the BAG3 polypeptide or fragment thereof is linked to another polypeptide.

12 . A method of identifying and treating a heart disease patient having a worse prognosis, comprising: screening a patient sample for the presence of a Bcl2-associated anthanogene 3 (BAG3) nucleotide variant (NV) in-frame insertion as compared to a control BAG3 nucleic acid sequence, wherein the BAG3 NV in-frame insertion comprises a 3 nucleotide insertion that adds an alanine at position 160 (p.Ala160dup, 10:121429647 A/AGCG; rs139438727) or a single nucleotide variant (SNV) in-frame insertion comprising: p.Pro63Ala (10:121429369 C/G; rs133031999); p.His83Gln (10:151331972; rs151331972); Ala479Val (10:121436502 C/T; rs34656239) or combinations thereof, wherein detection of the BAG3 NV in-frame insertion identifies the heart disease patient as having a worse prognosis compared to a nonischemic patient who does not have a same BAG3 NV in-frame insertion, and administering to the patient identified as having a worse prognosis a therapeutically effective amount of a BAG3 protein or biologically active fragment thereof or expression vector for expression of a BAG3 protein or biologically active fragment thereof.

13 . A method of identifying and treating a patient at risk of heart disease, comprising: screening a patient sample for the presence of a Bcl2-associated anthanogene 3 (BAG3) nucleotide variant (NV) in-frame insertion as compared to a control BAG3 nucleic acid sequence, wherein the BAG3 NV variant in-frame insertion comprises a 3 nucleotide insertion that adds an alanine at position 160 (p.Ala160dup, 10:121429647 A/AGCG; rs139438727) or a single nucleotide variant (SNV) in-frame insertion comprising: p.Pro63Ala (10:121429369 C/G; rs133031999); p.His83Gln (10:151331972; rs151331972); Ala479Val (10:121436502 C/T; rs34656239) or combinations thereof, wherein detection of the BAG3 NV in-frame insertion identifies the patient as being at risk of heart disease, and administering to the patient identified as at risk of heart disease a therapeutically effective amount of a BAG3 protein or biologically active fragment thereof or expression vector for expression of a BAG3 protein or biologically active fragment thereof.

14 . A method of treating a subject at risk of or suffering from heart failure comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a BAG3 protein or biologically active fragment thereof or expression vector for expression of a BAG3 protein or biologically active fragment thereof, wherein the subject has at least one BAG3 genetic variant as compared to a control BAG3 nucleic acid sequence, wherein the genetic variant comprises a 3 nucleotide insertion that adds an alanine at position 160 (p.Ala160dup, 10:121429647 A/AGCG; rs139438727) or a single nucleotide variant (SNV) in-frame insertion comprising: p.Pro63Ala (10:121429369 C/G; rs133031999); p.His83Gln (10:151331972; rs151331972); Ala479Val (10:121436502 C/T; rs34656239) or combinations thereof.

15 . The method of claim 14 , wherein the BAG3 polypeptide or fragment thereof is linked to another polypeptide.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 29, 2020
From: FELDMAN, ARTHUR M.
To: TEMPLE UNIVERSITY OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
Reel/Frame 054769/0495 →
Continuity (2)
Provisional Application 62682404 · Jun 8, 2018
Related Publication 20210254159A1 · Aug 19, 2021
References Cited (34)
US 11236389B2 · Feldman · 2022 [cited by examiner]
US 11542555B2 · Feldman · 2023 [cited by examiner]
US 20170016066A1 · Feldman et al. · 2017 [cited by applicant]
RU 2016107874A · 2017 [cited by applicant]
RU 2670133C2 · 2018 [cited by applicant]
WO 2012107580A1 · 2012 [cited by applicant]
WO WO2012107580 · 2012 [cited by examiner]
WO 2014078855A1 · 2014 [cited by applicant]
WO WO2015117010A2 · 2015 [cited by examiner]
WO 2017031182A2 · 2017 [cited by applicant]
VCV000178006 (from URL: ClinVar-NCBI); downloaded from the internet Jul. 24, 2024 (Year: 2016). [cited by examiner]
VCV000192113 (from URL: ClinVar-NCBI); downloaded from the internet Jul. 24, 2024 (Year: 2015). [cited by examiner]
Posafalvi, A. et al. “Clinical utility gene card for: dilated cardiomyopathy (CMD)”. European Journal of Human Genetics, vol. 21 (2013), p: doi:10.1038/ejhg.2012.276; published online Dec. 19, 2012. (Year: 2012). [cited by examiner]
Chami, N. et al. “Nonsense mutations in BAG3 are associated with Early-Onset Dilated Cardiomyopathy in French Canadians” Canadian Journal of Cardiology, vol. 30 (2014), pp. 1655-1661. (Year: 2014). [cited by examiner]
d'Avenia, M. et al. “A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy”. Cell Death and Disease, vol. 6 (2015), p: doi: … [cited by examiner]
Toro, R. et al. “Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene ” PLoS ONE, (2016) DOI: 10.1371/jounal.pone.0158730 . (Year: 2016). [cited by examiner]
Pei, N. et al. “Gene Expression Profiling Associated with Angiotensin II Type 2 Receptor-Induced Apoptosis in Human Prostate Cancer Cells ” PLoS ONE, vol. 9 (3)(2014), p: e92253. (Year: 2014). [cited by examiner]
Song,S. et al.“Activation of heat shock factor 1 plays a role in pyrrolidine dithiocarbamate-mediated expression of the co-chaperone BAG3.”The International Journal of Biochemistry & Cell Biology, vol. 42 (2010), pp. 18… [cited by examiner]
Knezevic, T. et al. “Adeno-Associated Virus Serotype 9-Driven Expression of BAG3 Improves Left Ventricular Function in Murine Hearts With Left Ventricular Dysfunction. ”JACC: Basic to Translational Science, vol. 1 (2016… [cited by examiner]
Bish, et al., Adeno-Associated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat, Human Gene Therapy, Nov. 28, 2008, 19(12):1359-1368. [cited by applicant]
Ranek, et al., The role of heat shock proteins and co-chaperones in heart failure, Philosophical Transactions of the Royal Society B: Biological Sciences, Jan. 19, 2018, 373(1738):1-18. [cited by applicant]
NM_004281.4 (BAG3): c468GGC[4] (p.Ala160dup) AND Dilated Cardiomyopathy, Dominant, Accession: RCV000261469.1. [cited by applicant]
NM_004281.4 (BAG3): c.187C_G (p.Pro63Ala) AND Cardiovascular Phenotype, Accession: RCV000618458.2. [cited by applicant]
NM_004281.4 (BAG3): c.187C_G (p.Pro63Ala), Accession: VCV000178006.28. [cited by applicant]
NM_004281.4 (BAG3): c.249C_G (p.His83GIn), Accession: VCV000044782.42. [cited by applicant]
NM_004281.4 (BAG3): c.1138C>T (p.Pro380Ser), Accession: RVC000437120.4. [cited by applicant]
NM_004281.4 (BAG3)_c.1436C_T (p.Ala479Val) and Myofibrillar Myopathy, Dominant, Accession: RCV000359990.1. [cited by applicant]
NM_004281.3 (BAG3)_c.1436C_T (p.Ala479Val), Accession: VCV000192113.22. [cited by applicant]
Ng D., et al., iInterpreting Secondary Cardiac Disease Variants in an Exome Cohort, Circ Cardiovasc Genet, Aug. 2013, 6:337-346 and Supplemental Material, 306 total pages. [cited by applicant]
Fernlund, E., et al., Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death, Pediatric Cardiology, Feb. 18, 2017, 38:1262-1268. doi:10.1007/s00246… [cited by applicant]
Franaszczyk, M., et al., The BAG3 gene variants in Polish patients with dilated cardiomyopathy: four novel mutations and a genotype-phenotype correlation, Journal of Translational Medicine, 2014, 12(192):1-8 [http://www… [cited by applicant]
Myers, Valerie D., Ph.D., The Role of BAG3 in the Failing Heart, Thesis of Temple University Graduate School, May 31, 2018. [cited by applicant]
Myers, V.D., et al., Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals. JAMA Cardiology, Oct. 1, 2018, vol. 3, No. 10, pp. 929. [cited by applicant]
Russian Application No. 2020143890, Office Action dated May 27, 2024 with English Translation of same. [cited by applicant]