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Recent Patents on Biotechnology


ISSN (Print): 1872-2083
ISSN (Online): 2212-4012

Review Article

Hutchinson-Gilford Progeria Syndrome (Hgps) and Application of Gene Therapy Based Crispr/Cas Technology as A Promising Innovative Treatment Approach

Author(s): Mekha Rajeev, Chameli Ratan, Karthik Krishnan and Meenu Vijayan*

Volume 15, Issue 4, 2021

Published on: 28 September, 2021

Page: [266 - 285] Pages: 20

DOI: 10.2174/1872208315666210928114720

Price: $65


Background: Hutchinson-Gilford progeria syndrome (HGPS), also known as progeria of childhood or progeria is a rare, rapid, autosomal dominant genetic disorder characterized by premature aging which occurs shortly after birth. HGPS occurs as a result of de novo point mutation in the gene recognized as LMNA gene that encodes two proteins, Lamin A protein and Lamin C protein which are the structural components of the nuclear envelope. Mutations in the gene trigger abnormal splicing and induce internal deletion of 50 amino acids leading to the development of a truncated form of Lamin A protein known as Progerin. Progerin generation can be considered the crucial step in HGPS since the protein is highly toxic to human cells, permanently farnesylated, and exhibits variation in several biochemical and structural properties within the individual. HGPS also produces complications such as skin alterations, growth failure, atherosclerosis, hair and fat loss, and bone and joint diseases. We have also revised all relevant patents relating to Hutchinson-Gilford progeria syndrome and its therapy in the current article.

Methods: The goal of the present review article is to provide information about Hutchinson- Gilford progeria syndrome (HGPS) and the use of CRISPR/Cas technology as a promising treatment approach in the treatment of the disease. The review also discusses about different pharmacological and non-pharmacological methods of treatment currently used for HGPS.

Results: The main limitation associated with progeria is the lack of a definitive cure. The existing treatment modality provides only symptomatic relief. Therefore, it is high time to develop a therapeutic method that hastens premature aging in such patients.

Conclusion: CRISPR/Cas technology is a novel gene-editing tool that allows genome editing at specific loci and is found to be a promising therapeutic approach for the treatment of genetic disorders such as HGPS where dominant-negative mutations take place.

Keywords: Hutchinson-gilford progeria syndrome (HGPS), LMNA gene, progerin, CRISPR/CAS system, lamin A protein, lamin C protein.

Graphical Abstract
Sharma V, Shukla R. Progeria: A rare genetic syndrome. Indian J Clin Biochem 2020; 35(1): 3-7.
[] [PMID: 32071491]
Ullrich N, Islam E. Gordon L. Hutchinson-Gilford progeria syndrome Islam MP, Roach ES, Eds Handbook of Clinical Neurology 3rd ed Amsterdam, Netherlands: Elsevier BV 2015; ;pp. 249-.
Kreienkamp R, Gonzalo S. Metabolic Dysfunction in Hutchinson-Gilford progeria syndrome. Cells 2020; 9(2): 395.
[] [PMID: 32046343]
Prokocimer M, Barkan R, Gruenbaum Y. Hutchinson-Gilford progeria syndrome through the lens of transcription. Aging Cell 2013; 12(4): 533-43.
[] [PMID: 23496208]
Aguado J, Sola-Carvajal A, Cancila V, et al. Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford progeria syndrome. Nat Commun 2019; 10(1): 4990.
[] [PMID: 31740672]
Arancio W. Hutchinson Gilford progeria syndrome: A therapeutic approach via adenoviral delivery of CRISPR/Cas genome editing system. J Genet Syndr Gene Ther 2014; 6: 1.
Santiago-Fernández O, Osorio FG, Quesada V, et al. Development of a CRISPR/Cas9-based therapy for Hutchinson-Gilford progeria syndrome. Nat Med 2019; 25(3): 423-6.
[] [PMID: 30778239]
Hutchinson J. Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Med Chir Trans 1886; 69: 473-7.
[] [PMID: 20896687]
Gilford H. Progeria: A form of senilism. Practitioner 1904; 73: 188-217.
Yu QX, Zeng LH. Progeria: Report of a case and review of the literature. J Oral Pathol Med 1991; 20(2): 86-8.
[] [PMID: 2016699]
Hennekam RC. Hutchinson-Gilford progeria syndrome: Review of the phenotype. Am J Med Genet A 2006; 140(23): 2603-24.
[] [PMID: 16838330]
Cision PR Newswire. Find the Children - 60 in India with Progeria' Campaign reignites the search for Children with Progeria in India. 2019; Available from:
Coutinho HD, Falcão-Silva VS, Gonçalves GF, da Nóbrega RB. Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model. Immun Ageing 2009; 6: 4.
[] [PMID: 19379495]
Broers JL, Ramaekers FC, Bonne G, Yaou RB, Hutchison CJ. Nuclear lamins: Laminopathies and their role in premature ageing. Physiol Rev 2006; 86(3): 967-1008.
[] [PMID: 16816143]
Domínguez-Gerpe L, Araújo-Vilar D. Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes. Curr Aging Sci 2008; 1(3): 202-12.
[] [PMID: 20021393]
Burke B, Stewart CL. The laminopathies: The functional architecture of the nucleus and its contribution to disease. Annu Rev Genomics Hum Genet 2006; 7: 369-405.
[] [PMID: 16824021]
Worman HJ, Ostlund C, Wang Y. Diseases of the nuclear envelope. Cold Spring Harb Perspect Biol 2010; 2(2): a000760.
[] [PMID: 20182615]
Barbara J. New hope for progeria: Drug for rare aging disease. Sci Am 2008; 8: 2-7.
Secerbegovic S. A hypothesis that aging results from defects in genetically produced proteins. Med Hypotheses 1997; 48(6): 531-3.
[] [PMID: 9247899]
Furukawa K, Inagaki H, Hotta Y. Identification and cloning of an mRNA coding for a germ cell-specific A-type lamin in mice. Exp Cell Res 1994; 212(2): 426-30.
[] [PMID: 8187835]
Machiels BM, Zorenc AH, Endert JM, et al. An alternative splicing product of the lamin A/C gene lacks exon 10. J Biol Chem 1996; 271(16): 9249-53.
[] [PMID: 8621584]
Weber K, Plessmann U, Traub P. Maturation of nuclear lamin A involves a specific carboxy-terminal trimming, which removes the polyisoprenylation site from the precursor; implications for the structure of the nuclear lamina. FEBS Lett 1989; 257(2): 411-4.
[] [PMID: 2583287]
Sinensky M, Fantle K, Trujillo M, McLain T, Kupfer A, Dalton M. The processing pathway of prelamin A. J Cell Sci 1994; 107(Pt 1): 61-7.
[] [PMID: 8175923]
Kilic F, Dalton MB, Burrell SK, Mayer JP, Patterson SD, Sinensky M. In vitro assay and characterization of the farnesylation-dependent prelamin A endoprotease. J Biol Chem 1997; 272(8): 5298-304.
[] [PMID: 9030603]
Capell BC, Collins FS. Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 2006; 7(12): 940-52.
[] [PMID: 17139325]
Tilli CM, Ramaekers FC, Broers JL, Hutchison CJ, Neumann HA. Lamin expression in normal human skin, actinic keratosis, squamous cell carcinoma and basal cell carcinoma. Br J Dermatol 2003; 148(1): 102-9.
[] [PMID: 12534602]
McClintock D, Gordon LB, Djabali K. Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody. Proc Natl Acad Sci USA 2006; 103(7): 2154-9.
[] [PMID: 16461887]
Reddel CJ, Weiss AS. Lamin A expression levels are unperturbed at the normal and mutant alleles but display partial splice site selection in Hutchinson-Gilford progeria syndrome. J Med Genet 2004; 41(9): 715-7.
[] [PMID: 15342704]
Fong LG, Ng JK, Lammerding J, et al. Prelamin A and lamin A appear to be dispensable in the nuclear lamina. J Clin Invest 2006; 116(3): 743-52.
[] [PMID: 16511604]
Ashapkin VV, Kutueva LI, Kurchashova SY, Kireev II. Are there common mechanisms between the Hutchinson-Gilford progeria syndrome and natural aging? Front Genet 2019; 10: 455.
[] [PMID: 31156709]
Huang S, Risques RA, Martin GM, Rabinovitch PS, Oshima J. Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A. Exp Cell Res 2008; 314(1): 82-91.
[] [PMID: 17870066]
Benson EK, Lee SW, Aaronson SA. Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J Cell Sci 2010; 123(Pt 15): 2605-12.
[] [PMID: 20605919]
Cao K, Blair CD, Faddah DA, et al. Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J Clin Invest 2011; 121(7): 2833-44.
[] [PMID: 21670498]
Aliper AM, Csoka AB, Buzdin A, et al. Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells. Aging (Albany NY) 2015; 7(1): 26-37.
[] [PMID: 25587796]
Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev 2007; 21(24): 3244-57.
[] [PMID: 18055696]
Osorio FG, Bárcena C, Soria-Valles C, et al. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response. Genes Dev 2012; 26(20): 2311-24.
[] [PMID: 23019125]
Csoka AB, English SB, Simkevich CP, et al. Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell 2004; 3(4): 235-43.
[] [PMID: 15268757]
Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP, Hegele RA. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J Med Genet 2004; 41(4): 304-8.
[] [PMID: 15060110]
Plasilova M, Chattopadhyay C, Pal P, et al. Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. J Med Genet 2004; 41(8): 609-14.
[] [PMID: 15286156]
Cao H, Hegele RA. LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet 2003; 48(5): 271-4.
[] [PMID: 12768443]
Sharma B, Sharma P, Joshi SC. Risk factors, prevalence and diagnosis of Hutchison Gilford syndrome with special reference to case reports. Int J Pharm Pharm Sci 2003; 9: 1-5.
Chaithanya KJ, Spurthi BS. Narayan, Sah. Sonar. A review: Progeria, the young who die old. World J Pharm Res 2020; 9: 1225-41.
Camacho-Cruz J, Dary Gutiérrez-Castañeda L. Hutchinson-Gilford progeria syndrome. Int J Pediatr 2019; 7: 10283-9.
Saxena S, Kumar S. Pharmacotherapy to gene editing: Potential therapeutic approaches for Hutchinson-Gilford progeria syndrome. Geroscience 2020; 42(2): 467-94.
[] [PMID: 32048129]
Baek J-H, McKenna T, Eriksson M. Hutchinson Gilford progeria syndrome. In: Puiu M, Ed. Genetic Disorider United Kingdom: IntechOpen 2013; 65-87.
Gupta KL, Anurag S. Hutchinson-Gilford progeria syndrome- A brief introduction. Int J Pharmc Res 2018; 8: 40-6.
Ullrich NJ, Gordon LB. Hutchinson-Gilford progeria syndrome. Handb Clin Neurol 2015; 132: 249-64.
[] [PMID: 26564085]
Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. In: M. P. Adam, Ed. GeneReviews® Seattle: University of Washington. 2003.
The Progeria Handbook; A Guide for Families and Health Care Providers of Children with Progeria. The Progeria Research Foundation. Available from: handbook/
Leslie Gordon MD, Lisa MacDonnell RPT. Information for families and caretakers from the Progeria Research Foundation. Physical therapy and occupational therapy in Progeria. 2019; Available from:
Mohanty S, Vaidyanathan B. Anti-platelet agents in pediatric cardiac practice. Ann Pediatr Cardiol 2013; 6(1): 59-64.
[] [PMID: 23626438]
Piekarowicz K, Machowska M, Dzianisava V, Rzepecki R. Hutchinson-Gilford progeria syndrome-current status and prospects for gene therapy treatment. Cells 2019; 8(2): 88.
[] [PMID: 30691039]
Harhouri K, Frankel D, Bartoli C, Roll P, De Sandre- Giovannoli A, Lévy N. An overview of treatment strategies for Hutchinson-Gilford progeria syndrome. Nucleus 2018; 9(1): 246-57.
[] [PMID: 29619863]
Yang SH, Chang SY, Andres DA, Spielmann HP, Young SG, Fong LG. Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria. J Lipid Res 2010; 51(2): 400-5.
[] [PMID: 19965595]
Rahman Md. The Hutchinson-Gilford progeria syndrome and treatment: Updated review of the literature. Sch Acad J Pharm 2020; 9: 68-74.
Lai WF, Wong WT. Progress and trends in the development of therapies for Hutchinson-Gilford progeria syndrome. Aging Cell 2020; 19(7): e13175.
[] [PMID: 32596971]
Sugunan AH, Anila A, Nair KN, Sasidharan GV. Premature ageing in children: A rare genetic disorder called progeria. Int J Pharm Res 2020; 122(2): 29-36.
Gordon LB, Kleinman ME, Miller DT, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 2012; 109(41): 16666-71.
[] [PMID: 23012407]
Gordon A, Gordon L. The Progeria Research Foundation: Its remarkable journey from obscurity to treatment. Expert Opin Orphan Drugs 2014; 2: 1187-95.
Sadaf S. Treatment strategies for toxic protein progerin: Hutchinson- Gilford progeria syndrome. J Clin Med Sci 2020; 4: 116.
Solenn M. Hutchinson-Gilford progeria syndrome: Rejuvenating old drugs to fight accelerated ageing. Methods 2020; 190: 3-12.
[] [PMID: 32278808]
Strandgren C, Revêchon G, Sola-Carvajal A, Eriksson M. Emerging candidate treatment strategies for Hutchinson-Gilford progeria syndrome. Biochem Soc Trans 2017; 45(6): 1279-93.
[] [PMID: 29127216]
Varela I, Pereira S, Ugalde AP, et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med 2008; 14(7): 767-72.
[] [PMID: 18587406]
Mendelsohn AR, Larrick JW. Rapamycin as an antiaging therapeutic?: Targeting mammalian target of rapamycin to treat Hutchinson-Gilford progeria and neurodegenerative diseases. Rejuvenation Res 2011; 14(4): 437-41.
[] [PMID: 21851176]
Evangelisti C, Cenni V, Lattanzi G. Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria-related disorders. Br J Clin Pharmacol 2016; 82(5): 1229-44.
[] [PMID: 26952863]
Lee JM, Nobumori C, Tu Y, et al. Modulation of LMNA splicing as a strategy to treat prelamin A diseases. J Clin Invest 2016; 126(4): 1592-602.
[] [PMID: 26999604]
Harhouri K, Navarro C, Baquerre C, et al. Antisense-based progerin downregulation in HGPS-like patient’s cells. Cells 2016; 11: 5-31.
Xiong ZM, Choi JY, Wang K, et al. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell 2016; 15(2): 279-90.
[] [PMID: 26663466]
Kubben N, Zhang W, Wang L, et al. Repression of the antioxidant NRF2 pathway in premature aging. Cell 2016; 165(6): 1361-74.
[] [PMID: 27259148]
Pike JW, Meyer MB, Lee SM, Onal M, Benkusky NA. The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J Clin Invest 2017; 127(4): 1146-54.
[] [PMID: 28240603]
Ghosh S, Liu B, Zhou Z. Resveratrol activates SIRT1 in a Lamin A-dependent manner. Cell Cycle 2013; 12(6): 872-6.
[] [PMID: 23439428]
Richards SA, Muter J, Ritchie P, Lattanzi G, Hutchison CJ. The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine. Hum Mol Genet 2011; 20(20): 3997-4004.
[] [PMID: 21807766]
Park SK, Shin OS. Metformin alleviates ageing cellular phenotypes in Hutchinson-Gilford progeria syndrome dermal fibroblasts. Exp Dermatol 2017; 26(10): 889-95.
[] [PMID: 28192606]
Rodríguez-Rodríguez DR, Ramírez-Solís R, Garza-Elizondo MA, Garza-Rodríguez ML, Barrera-Saldaña HA. Genome editing: A perspective on the application of CRISPR/Cas9 to study human diseases. Int J Mol Med 2019; 43(4): 1559-74.
[] [PMID: 30816503]
Sampson TR, Weiss DS. Exploiting CRISPR/Cas systems for biotechnology. BioEssays 2014; 36(1): 34-8.
[] [PMID: 24323919]
Munoz IM, Szyniarowski P, Toth R, Rouse J, Lachaud C. Improved genome editing in human cell lines using the CRISPR method. PLoS One 2014; 9(10): e109752.
[] [PMID: 25303670]
O’Connell MR, Oakes BL, Sternberg SH, East-Seletsky A, Kaplan M, Doudna JA. Programmable RNA recognition and cleavage by CRISPR/Cas9. Nature 2014; 516(7530): 263-6.
[] [PMID: 25274302]
Kay MA. State-of-the-art gene-based therapies: the road ahead. Nat Rev Genet 2011; 12(5): 316-28.
[] [PMID: 21468099]
Cheng R, Peng J, Yan Y, et al. Efficient gene editing in adult mouse livers via adenoviral delivery of CRISPR/Cas9. FEBS Lett 2014; 588(21): 3954-8.
[] [PMID: 25241167]
Ding Q, Strong A, Patel KM, et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res 2014; 115(5): 488-92.
[] [PMID: 24916110]
Musunuru K. Adenine base editing to treat progeria syndrome and extend the lifespan. J Cardiovasc Aging 2021; 1: 8.
[] [PMID: 34308436]
Kantor A, McClements ME, MacLaren RE. CRISPR-Cas9 DNA base-editing and prime-editing. Int J Mol Sci 2020; 21(17): 6240.
Kole R, Collins FS, Erdos MR, Cao K, Gordon LB. Methods for treating progeroid laminopathies using oligonucleotide analogues targeting human LMNA. US Patent 10398721, 2021.
Eriksson BMH, Collins FS, Gordon LB, Brown TD. Gene and its involvement in Hutchinson-Gilford Progeria Syndrome (HGPS) and arteriosclerosis. US Patent 9115400, 2021.
Gordon LB, Collins FS, Glover T, et al. Farnesyltransferase inhibitors for treatment of laminopathies, cellular aging and atherosclerosis. US Patent 8828356, 2021.

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