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

Abstract

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 as 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. Method: 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.

Pediatric Premature Aging Diseases

“…Onset is after 2 years of age, alive a long lifespan. A LMNA/ ZMPSTE24 mutation is responsible for the extremely rare disease in childhood [13][14][15]. Werner Syndrome is a defect in the WRN gene on short arm of chromosome 8 (p12-p11.2), a chromosome break syndrome.…”

The Role of Klotho in Pediatric Premature Aging Diseases

“…Hutchinson-Gilford-Progeria (Joseph Syndrome, progeria syndrome): HGPS is an early-onset premature aging disorder that occurs approximately in 1:4 to 8 million live births and has been reported in more than 250 cases worldwide [6,1,2,[17][18][19]22,[62][63][64][65][66][67][68][69][70][71][72]. The prevalence is estimated at 1:4,000,000-1:8000000.…”

“…The prevalence is estimated at 1:4,000,000-1:8000000. Patients die at a mean age of 12.6 years mostly due to progressive atherosclerosis and cardiovascular diseases [6,1,2,[17][18][19]22,[62][63][64][65][66][67][68][69][70][71][72]. It belongs to the segmental progeroid syndromes (SPS; rare diseases with signs of premature aging in more than one organ or tissue) or progeria syndromes and is a clinical sign of various hereditary diseases associated with rapid aging in children [6,1,2,[17][18][19]22,[62][63][64][65][66][67][68][69][70][71][72].…”

“…Patients die at a mean age of 12.6 years mostly due to progressive atherosclerosis and cardiovascular diseases [6,1,2,[17][18][19]22,[62][63][64][65][66][67][68][69][70][71][72]. It belongs to the segmental progeroid syndromes (SPS; rare diseases with signs of premature aging in more than one organ or tissue) or progeria syndromes and is a clinical sign of various hereditary diseases associated with rapid aging in children [6,1,2,[17][18][19]22,[62][63][64][65][66][67][68][69][70][71][72]. The Hutchinson-Gilford syndrome is an autosomal-dominant disease of various tissues that leads to a massive and very early onset of aging of the skin, skeleton and blood vessels in early childhood [62][63][64][65][66][67][68][69][70][71]…”

“…Werner syndrome and Bloom syndrome both arise due to DNA helicase gene mutations resulting in growth deficiency and a predisposition to malignancy, amongst other features [38][39][40][41][42][43][44]. Another mechanism of premature ageing arises in the progeroid laminopathies whereby aberrant lamin A processing leads to the accumulation of progerin in the cell nucleus, variably causing severe growth retardation, accelerated ageing, skeletal abnormalities and early death from cardiovascular disease [6,1,2,[17][18][19]22,[62][63][64][65][66][67][68][69][70][71][72].…”