Annotated Bibliography

Capell, Brian C., et al. “A farnesyltransferase inhibitor prevents both the onset and late   progression of cardiovascular disease in a progeria mouse model.” Proceedings of                        the National Academy of Sciences 105.41 (2008): 15902-15907.

Almost all cases of HGPS are caused by a de novo point mutation in the lamin A (LMNA) gene that results in production of a mutant laminA protein termed progerin. This protein is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has been shown to prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. We have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. Here we show that the dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease.

Dietz, Harry C. “New therapeutic approaches to mendelian disorders.” New England                  Journal of Medicine 363.9 (2010): 852-863.

The overarching task of this article was to focus on therapeutic strategies that exploit a precise understanding of the pathogenesis of a mendelian disease, giving examples that illustrate the strengths and limitations of each approach, as well as the potential for broadening its application to the treatment of more common disorders. When Dietz took a closer look at Hutchinson-Gilford progeria the results brought more questions to the surface. Because alterations in nuclear morphologic characteristics reminiscent of those in patients with the Hutchinson–Gilford progeria syndrome are also seen in patients with other conditions caused by mutations in LMNA thatneither alter processing of pre–lamin A nor are associated with premature features of aging, it re- mains unclear whether nuclear blebbing is an informative surrogate for critical phenotypes of the Hutchinson–Gilford progeria syndrome. Moreover, it is possible that more relevant pathogenic mechanisms depend on an inability of progerin to support the essential nuclear functions carried out by mature (processed) lamin A.

Gordon, Leslie B., et al. “Progeria: a paradigm for translational medicine.” Cell 156.3     (2014): 400-407.

Gordon’s article offers insight to how rare diseases are used as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have.Many of the hot topics in the field have both a basic and translatable clinical component, and the basic-clinical connection will be driving much of the future work. A roadmap becomes evident for optimizing the chances of tackling a disease once its molecular basis is uncovered. Due to the fact that Hutchinson-Gilford progeria syndrome is a premature aging syndrome we are able to take a look at the diagnosed and relate it to what should be a normal aging process in those without HGPS.Much like in normal aging, tissue functions appear to be compromised in HGPS. A window into aging related cardiovascular disease is opened. Evidence supports the hypothesis that progerin levels increase with age promoting vascular calcification.The prominence of the vascular defects in progeria may provide an interesting model system to explore the effectiveness of tissue-targeted approaches in systemic diseases.

Liu, Guang-Hui, et al. “Recapitulation of premature ageing with iPSCs from Hutchinson-          Gilford progeria syndrome.” Nature 472.7342 (2011): 221-225.

HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin. In thisreport, the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing.Because progerin also accumulates during physiological ageing^{6, 12, 13}, our results provide an in vitroiPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.

Makous, Norman, et al. “Cardiovascular manifestations in progeria. Report of clinical     and pathologic findings in a patient with severe arteriosclerotic heart disease and                       aortic stenosis.” American heart journal 64.3 (1962): 334-346.

The case of a 12-year-old boy with progeria, which was previously reported during his lifetime, is presented again, but this time with postmortem findings and with emphasis on the cardiovascular abnormalities. Death resulted from coronary artery atheromatosis and insufficiency, interstitial myocardial fibrosis, and calcific aortic stenosis.

The 31 other typical cases of progeria reported in the literature since 1886 are reviewed with respect to the clinical and pathologic findings in the cardiovascular system. From this review, the natural course of cardiovascular events in progeria has been reconstructed. Cardiac murmurs usually appear after the patients are 5 years old; subsequently, diastolic systemic hypertension, cardiomegaly, and hypercholesterolemia develop. Death from cardiac complications at an average age of 14 years is usually preceded by angina pectoris, myocardial infarction, or congestive heart failure.

Merideth, Melissa A., et al. “Phenotype and course of Hutchinson–Gilford progeria                    syndrome.” New England Journal of Medicine 358.6 (2008): 592-604.

In this journal article researchersenrolled 15 children between 1 and 17 years of age, representing nearly half of the world’s known patients with Hutchinson–Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006.The results confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented.Other than the predicted findings, the clinical investigations came across new discoveries including prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits.The researchers concluded that establishing the detailed phenotype of Hutchinson–Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)During this clinical protocol cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle–brachial indexes, and adventitial thickening.

MONGA, DIMPLE, SIDHARTH MEHAN, and DEEPA KHANNA. “HUTCHINSON                      GILFORD PROGERIA SYNDROME: A FUTURE PARADIGM FOR DRUG      DISCOVERY.”

This paper provides the effects of the disease progeria on the health of the people in the world and its current treatments.Hutchinson Gilford Progeria Syndrome (HGPS; MIM 176670), is an extremely rare, sporadic genetic syndrome that characterized by premature aging of children with an estimated incidence of 1 per 4-8 millions live births. The major typically symptoms include failure to thrive, severe growth retardation, hair loss, scleroderma-like skin, diminished subcutaneous fat, prominent eyes, and prominent scalp veins, absent sexual maturation, reduced bone density and premature atherosclerosis. The cardiovascular diseases are the most serious aspect, because individuals with HGPS generally die at an average age of 11-13 years due to myocardial infarction, heart failure or cerebrovascular accident caused by progressive atherosclerotic disease. The incidence of HGPS is 1 in 4 million births. HGPS is associated with accumulation of DNA lesion and defect in DNA damage repair mechanism. HGPS remains incurable, with no therapy other than symptomatic treatment. Hydrotherapy promotes relaxation, relieves pain, assists movement and enables exercise. It can also help prevent arthritis from getting worse. Enrich diet prevent the progeria like nutrini, pro-cal, vitamin E. Rapamycin minimize the phenotypic effects of progeria& abolishment of nuclear blebbing. Farnesylationtransferase inhibitors are drugs that inhibit the activity of an enzyme needed in order to make a link between progerin proteins and farnesyl groups. By better understanding the mechanisms of HGPS, it may be possible to minimize the pathological process observed in HGPS, and to develop potential treatments for age-related disease.

Olive, Michelle, et al. “Cardiovascular pathology in Hutchinson-Gilford progeria:                                   correlation with the vascular pathology of aging.” Arteriosclerosis, thrombosis,                      and vascular biology 30.11 (2010): 2301-2309.

The objective of this study was to create the first histological comparative evaluation between genetically confirmed HGPS and the cardiovascular disease of aging.The methods and results were to present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an averageof 3.34% per year (P<0.0001) in coronary arteries.The research concluded that concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients. HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population.

Part B: Brief Research Proposal

The question that became evident was: Does progeria open a window into aging related cardiovascular disease? Hutchinson-Gilford progera syndrome is characterized as an extremely rare genetic disorder that causes premature, rapid aging shortly after birth.Due to the fact that HGPS constitutes aging, researchers are taking into account that it may be an opportunity to find new treatments for cardiovascular and other aging related diseases. It is affectionately called a paradigm for new therapeutic approaches. Although it is amongst the rarest diseases known to man, new discoveries about progeriaarise everyday.