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A targeted antisense therapeutic approach for Hutchinson–Gilford progeria syndrome

Nature Medicine volume 27, pages 536–545 (2021)Cite this article

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Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.

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Fig. 1: Design and testing of a PPMO-based strategy for blocking the production of progerin.
Fig. 2: Effect of SRP-2001 on cellular proliferation and B-type lamin protein expression in the fibroblasts of a patient with HGPS.
Fig. 3: Determination of SRP-2001 efficacy in culture.
Fig. 4: Efficient in vivo delivery of PPMO to murine vascular cells and tissues.
Fig. 5: Long-term treatment of HGPS mice with SRP-2001 significantly extends their lifespan.
Fig. 6: Partial rescue of vascular tissue degradation in mice treated with SRP-2001.

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All requests for raw and analyzed data and materials will be promptly reviewed by the National Human Genome Research Institute and Sarepta Therapeutics to verify whether the request is subject to any intellectual property or confidentiality obligations. Any data and materials that can be shared will be released via a Data/Material Sharing Agreement. All requests should be made to the primary or corresponding author. All detailed PPMO sequence and assay primer data are presented in the extended and supplementary data.

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Acknowledgements

This work was supported by the NIH Intramural Research Program. F.S.C., M.R.E., W.A.C., J.G.-J., Y. B. and U.L.T. were funded by the National Human Genome Research Institute (no. HG200305). K.C. was supported by NIHR01 HL126784. F.S.C. and J.G.-J. were funded by a Progeria Research Foundation grant (no. 2015-57). L.B.G. was funded by the Progeria Research Foundation. We thank T. Yan for assistance with data analysis.

Author information

Author notes

  1. These authors contributed equally: Michael R. Erdos, Wayne A. Cabral.

Authors and Affiliations

  1. Molecular Genetics Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Michael R. Erdos, Wayne A. Cabral, Urraca L. Tavarez, Jelena Gvozdenovic-Jeremic, Narisu Narisu, Yoseph Boku & Francis S. Collins

  2. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA

    Kan Cao

  3. Diagnostic and Research Services Branch, Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD, USA

    Patricia M. Zerfas & Michael A. Eckhaus

  4. Sarepta Therapeutics, Inc., Cambridge, MA, USA

    Stacy Crumley, Gunnar Hanson & Ryszard Kole

  5. Department of Veterinary Health Science, Oregon State University, Corvallis, OR, USA

    Dan V. Mourich

  6. Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA

    Ryszard Kole

  7. Department of Pediatrics, Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA

    Leslie B. Gordon

  8. Department of Anesthesiology, Preoperative and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA

    Leslie B. Gordon

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Contributions

M.R.E, W.A.C., G.H., D.V.M., R.K., K.C., U.L.T. and F.S.C. designed the research. M.R.E., W.A.C., K.C., J.G.-J., S.C. and U.L.T. performed the experiments. M.R.E., W.A.C., K.C., N.N., P.M.Z., S.C., Y.B. and M.A.E. analyzed the data. M.R.E., L.B.G. and F.S.C. supervised the project. M.R.E., W.A.C. and F.S.C. wrote the manuscript with input from all other authors.

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Correspondence to Francis S. Collins.

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Peer review information Nature Medicine thanks Thomas Glover and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Joao Monteiro was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 PPMO structure.

SRP-2001 is a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) comprising a cell-penetrating peptide (CPP) covalently linked to a phosphorodiamidate morpholino oligomer (PMO). The PMO contains 25 morpholino subunits each bearing a nucleobase forming the sequence 5’-GAGGAGATGGGTCCACCCACCTGGG-3’. The conjugated peptide comprises the amino acid sequence R6G, where R is arginine and G is glycine. The glycine residue covalently links the CPP to the PMO by an amide bound to the 3’ end of the PMO. Mass spectrometric characterization was performed to confirm the structure and sequence of SRP-2001.

Extended Data Fig. 2 Quantitative PCR screening of candidate PPMOs for targeted reduction of progerin in proband fibroblasts.

Quantitation of LMNA (A), Progerin (P), and LMNC (C) expression by ddPCR analysis of Classic HGPS (LMNA c.1824C > T) fibroblasts treated with 6uM candidate PPMOs. a, Transcript levels relative to TFRC. b, Each isoforms’ fraction relative to all LMNA transcripts. c, Each isoforms’ transcript level relative to LMNC transcripts. The greatest reduction of progerin transcripts in culture was achieved with the centrally located morpholino (SRP-2001). A, LMNA; P, Progerin; C, LMNC; WT, oligo complementary to normal LMNA sequence; CTRL, scrambled control; Values and error bars represent mean ± SD determined from triplicate reactions of biological triplicates. * p < 0.05, ** p < 0.01, *** p < 0.001 versus transcripts or protein from cells receiving saline (NT).

Extended Data Fig. 3 Western immunoblot screening of candidate PPMOs for targeted reduction of progerin in proband fibroblasts.

Quantitation of LMNA (A), Progerin (P), and LMNC (C) protein from immunoblots of lysates from Classic HGPS (LMNA c.1824C > T) fibroblasts treated with 6uM candidate PPMOs. Data was derived from the analysis shown in Fig. 1d and is expressed as isoform levels relative to ACTB (a), the isoforms’ fraction relative to all LMNA gene products (b), and the isoforms’ level relative to LMNC protein (c). The greatest reduction of progerin protein in culture was achieved with the centrally located morpholino (SRP-2001). A, LMNA; P, progerin; C, LMNC; WT, oligo complementary to normal LMNA sequence; CTRL, scrambled control; Values and error bars represent mean ± SD determined from biological triplicates shown in Fig. 1d. * p < 0.05, ** p < 0.01, *** p < 0.001 versus transcripts or protein from cells receiving saline NT).

Extended Data Fig. 4 Quantitative PCR screening of SRP-2001 for targeted reduction of progerin in Classic and Non-classic HGPS cell lines.

a, Transcript copy number in normal control (NL Control), Classic HGPS (c.1824C>T), and Non-classic HGPS (c.1822G>A, c.1968+1G>A, c.1968+2T>C, c.1968+5G>C) fibroblasts following 2 weeks of treatment with SRP-2001. b, Individual LMNA transcripts expressed as a fraction of all total LMNA-derived transcripts in each cell line. c, Full-length LMNA and progerin transcript levels relative to LMNC transcripts. A, LMNA; P, progerin; C, LMNC; Values and error bars represent mean ± SD determined from triplicate reactions of biological triplicates. * p < 0.05; ** p < 0.01; *** p < 0.001 vs same transcript in cells receiving saline only (NT).

Extended Data Fig. 5 Reduction of progerin protein by SRP-2001 in Classic and Non-classic HGPS cell lines.

a, Western immunoblots of normal control (NL Control), Classic HGPS (c.1824C>T), and Non-classic HGPS (c.1822G>A, c.1968+1G>A, c.1968+2T>C, c.1968+5G>C) fibroblasts following 2 weeks of treatment with SRP-2001. b, Quantitation of LMNA gene products relative to ACTB. c, Quantitation of LMNA, progerin and LMNC isoforms expressed as a fraction of all total LMNA-derived gene products in each cell line. d, Full-length LMNA and progerin protein levels relative to LMNC. A, LMNA; P, progerin; C, LMNC; Graphs represent mean ± SD determined from biological triplicates shown in panel A. * p < 0.05; ** p < 0.01; *** p < 0.001 vs same protein isoform in cells receiving saline only (NT).

Extended Data Fig. 6 SRP-2001 reduces expression of transgene-derived progerin in murine aortas.

a, Quantitative PCR analysis of transgene transcript levels in aortas of LMNAG/G mice receiving long-term treatment with saline (vehicle) or 60 mg/kg SRP-2001. Transcripts are quantitated relative to Hprt expression, as a fraction of all transgene-derived LMNA transcripts or relative to transgene-derived LMNC transcripts. Data are presented as mean values ± SD determined from 12 independent samples per treatment group (n = 6 males, 6 females). b, Western immunoblots of A-type lamins and beta actin (ACTB) immunoprecipitated from aorta tissue. c, Quantitation of A-type lamins from immunoblots expressed relative to beta actin (ACTB), as a fraction of all A-type lamins and relative to LMNC. Data are presented as mean values ± SD determined from 12 independent samples per treatment group (n = 6 males, 6 females), shown in panel b. A, LMNA; P, progerin; C, LMNC; * p < 0.05; ** p < 0.01; *** p < 0.001 vs same transcript or protein in mice receiving saline only (vehicle).

Extended Data Fig. 7 SRP-2001 reduces expression of transgene-derived progerin in murine hearts.

a, Quantitative PCR analysis of transgene transcript levels in hearts of LMNAG/G mice receiving long-term treatment with saline (vehicle) or 60 mg/kg SRP-2001. Transcripts are quantitated relative to Hprt expression, as a fraction of all transgene-derived LMNA transcripts or relative to transgene-derived LMNC transcripts. Data are presented as mean values ± SD determined from 12 independent samples per treatment group (n = 6 males, 6 females). b, Western immunoblots of A-type lamins and smooth muscle actin (SMA) immunoprecipitated from heart tissue. c, Quantitation of A-type lamins from immunoblots expressed relative to smooth muscle actin (SMA), as a fraction of all A-type lamins and relative to LMNC. Data are presented as mean values ± SD determined from 12 independent samples per treatment group (n = 6 males, 6 females), shown in panel b. A, LMNA; P, progerin; C, LMNC; * p < 0.05; ** p < 0.01; *** p < 0.001 vs same transcript or protein in mice receiving saline only (vehicle).

Extended Data Fig. 8 SRP-2001 reduces expression of transgene-derived progerin in murine liver.

a, Quantitative PCR analysis of transgene transcripts in liver tissue of LMNAG/G mice receiving long-term treatment with saline (vehicle) or 60 mg/kg SRP-2001. Expression of LMNA (A), progerin (P) and LMNC (C) is quantitated relative to Hprt expression, as a fraction of all transgene-derived LMNA transcripts or relative to transgene-derived LMNC transcripts. Data are presented as mean values ± SD determined from 12 independent samples per treatment group (n = 6 males, 6 females). b, Western immunoblots of A-type lamins and beta actin (ACTB) immunoprecipitated from liver homogenates. c, Quantitation of A-type lamins from immunoblots expressed relative to beta actin (ACTB), as a fraction of all A-type lamins and relative to LMNC. Data are presented as mean values ± SD determined from 12 independent samples per treatment group (n = 6 males, 6 females), shown in panel b. * p < 0.05; ** p < 0.01; *** p < 0.001 vs same transcript or protein in mice receiving saline only (vehicle).

Extended Data Fig. 9 SRP-2001 reduces progerin transcripts in multiple mesenchyme-derived murine tissues.

Quantitative PCR analysis of transgene transcripts in a, quadriceps, b, femoral bone, and c, kidneys of LMNAG/G mice receiving long-term treatment with saline (vehicle) or 60 mg/kg SRP-2001. Expression of LMNA (A), progerin (P) and LMNC (C) is quantitated relative to Hprt expression, as a fraction of all transgene-derived LMNA transcripts or relative to transgene-derived LMNC transcripts. Data are presented as mean values ± SD determined from 12 independent samples per treatment group (n = 6 males, 6 females). * p < 0.05; ** p < 0.01; *** p < 0.001 vs same transcript or protein in mice receiving saline only (vehicle).

Extended Data Fig. 10 Histologic analysis of kidneys shows minimal toxicity due to long-term treatment with SRP-2001.

Representative images of haemotoxylin and eosin (HE) staining of sectioned kidneys from treated (n = 12) and untreated (n = 12) mice. Mice receiving long-term treatment with SRP-2001 developed irregular cortical surfaces (ic), degenerate tubules (dt) and basophilic granules (bg) in tubular epithelial cells. Two sections per tissue sample were analyzed.

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Erdos, M.R., Cabral, W.A., Tavarez, U.L. et al. A targeted antisense therapeutic approach for Hutchinson–Gilford progeria syndrome. Nat Med 27, 536–545 (2021). https://doi.org/10.1038/s41591-021-01274-0

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