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Gene Therapy for Cardiovascular Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Dhwani Thakkar, Vandit Shah, Jigna Shah
In hyperlipidemia, gene therapy for atherosclerosis is potentially used for the treatment of lipoprotein metabolism. GLYBERA was the very first gene-based medication granted in the Western world for lipoprotein lipase deficiency and severe pancreatitis attacks. It was reported for lipoprotein lipase deficiency and severe pancreatitis attacks.69 Recently, various clinical trials using gene therapy are ongoing, with focus on lowering the plasma concentration level and homozygous familial hypercholesterolemia by targeting LDL receptors, lipoprotein (a) as mentioned in Table 6.2.66,70–72
Xanthelasma
Published in K. Gupta, P. Carmichael, A. Zumla, 100 Short Cases for the MRCP, 2020
K. Gupta, P. Carmichael, A. Zumla
These are: Eruptive xanthomas: these occur as firm, raised papules with pale yellow centres over the buttocks, elbows, knees and extensor aspect of the forearms. Associations include familial lipoprotein lipase deficiency, familial combined hyperlipidaemia and uncontrolled diabetes mellitus.Planar or palmar xanthomas: often yellow to orange in colour, being most commonly found in the palmar and digital creases. They occur in type III hyperlipidaemia.Tendon xanthomas: these occur in the extensor tendons on the hands, elbows, knees and ankles. Most are characteristic of familial hypercholesterolaemia.• Go over Fredrickson's or the WHO classification of hyperlipidaemias.
Lipoprotein lipase deficiency/type I hyperlipoproteinemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Lipoprotein lipase deficiency is autosomal recessive in inheritance. Occurrence in a number of siblings has been reported [2], as has consanguinity [9]. Lipoprotein lipase activity of about 50 percent of normal has been reported in adipose tissue of parents of patients with deficiency [31]. Low levels of a lipolytic activity have also been observed in postheparin plasma of relatives, but heterozygosity cannot always be demonstrated by assay of the plasma [13]. Heterozygotes may have hypertriglyceridemia [31], but fasting levels of triglycerides are usually normal. In fact, it has been demonstrated by careful study of an extended pedigree [13] that hypertriglyceridemia of many genetic and other causes is so common in adults that the finding of an elevated concentration of triglycerides in a parent or relative cannot be equated with heterozygosity for lipoprotein lipase deficiency.
Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome
Published in Expert Review of Clinical Pharmacology, 2018
Rabia Chaudhry, Adie Viljoen, Anthony S. Wierzbicki
It is more logical to define hypertriglyceridemia syndromes by their genetic etiology. Chylomicronemia syndrome is mostly caused by five genes affecting proteins relevant to the LPL metabolic pathway. Patients having mutations in two relevant alleles are homozygous or compound heterozygous and should be defined as having familial chylomicronemia syndrome (FCS) and strictly only the subset with mutations in LPL have lipoprotein lipase deficiency (LPLD) [4]. Many patients have reduced LPL activity, but LPL activity can be close to normal in patients with apoC2 deficiency or those who are dual gene heterozygotes [4]. Patients with single mutations are simple heterozygotes and may have reduced LPL activity and have partial LPL deficiency if the primary mutation is in LPL. However, many patients heterozygous for LPL pathway mutations are asymptomatic and have normal lipid profiles so the etiology of hypertriglyceridemia in such patients is likely to represent a more complex interaction of genes and environment. A further group of patients have severe polygenic TG elevations caused by variants at multiple genes with effects on TG metabolism and also can express a phenotype of partial LPL deficiency [5,6].
Nanotechnology-enabled gene delivery for cancer and other genetic diseases
Published in Expert Opinion on Drug Delivery, 2023
Tong Jiang, Karina Marie Gonzalez, Leyla Estrella Cordova, Jianqin Lu
Viral delivery systems utilize the natural characteristics that viruses can introduce their own genetic material into host cells, where the target genome is integrated with virus genes. Viral vectors include retroviruses, lentiviruses, adenoviruses and adeno-associated viruses, etc. Cells can be transfected efficiently because of the ability of utilizing the innate infectivity of wild-type viruses [30] to achieve a therapeutic effect. Most retroviruses are active only in dividing cells [31] and one of the features of retroviruses is that they can be incorporated into the cell genome, allowing stable expression of therapeutic genes [31] This prolonged-term expression can provide effective therapeutic effects while reducing the immune response to the host [32]. Lentivirus are a type of retrovirus that can infect both dividing and quiescent cells [33]. Compared with alternative viral vectors, lentiviruses have a larger capacity to carry additional complex genome, which can be integrated into host genome to achieve a stable long-term expression. The structural and biological properties of adenoviruses and adeno-associated viruses make them the most commonly used as a vector for gene therapy in current clinical trials [34]. AAV-based gene therapy agent Glybera, for example, has been indicated for adult patients with familial lipoprotein lipase deficiency treatment. Some progress has been made of viral vectors gene delivery, which is used in most cell and gene therapy projects. Nonetheless, there are still many limitations, such as carcinogenic effect, potential immunogenicity, poor specificity, difficulty in size adjust of virus, and complex preparation process with a high cost [35].
Evaluating the impact of peer support and connection on the quality of life of patients with familial chylomicronemia syndrome
Published in Expert Opinion on Orphan Drugs, 2018
Valerie Salvatore, Alan Gilstrap, Karren R Williams, Swati Thorat, Michael Stevenson, Andrea R Gwosdow, Andrew Hsieh, Brant C Hubbard, David Davidson
FCS, formerly referred to as lipoprotein lipase deficiency (LPLD) in some literature, is accompanied by significant disease burden, including acute pancreatitis, recurrent abdominal pain, hepatosplenomegaly, eruptive xanthomas, lipemia retinalis, and fatigue [2]. Acute pancreatitis presents the most significant risk in patients with FCS, with significant complications including potentially fatal acute pancreatitis [3]. Approximately 67% [4] to 76% [5] of patients with FCS have experienced acute pancreatitis. In a large prospective study [6] conducted in a cohort of 201 patients with acute pancreatitis, researchers showed that outcomes for patients with hypertriglyceridemia-induced acute pancreatitis are more severe with worse outcomes than pancreatitis of other etiologies. This study [6] demonstrated that compared to acute pancreatitis in patients with normal TG levels (< 150 mg/dL), the acute pancreatitis in patients with severe hypertriglyceridemia (TG > 1000 mg/dL) resulted in longer median hospital stays, increased need for intensive care, a higher rate of pancreatic necrosis, more frequent persistent organ failure, and higher rates of mortality [6]. Further, patients with LPLD may be at enhanced risk of pancreatitis compared to patients with moderately high TG (~440–800 mg/dL), and certainly in comparison with patients with normal TG levels. According to one study, in comparison with patients with normal TG levels, patients with LPLD with TG > 800 mg/dL had a 360-fold greater risk of acute pancreatitis, and a greater risk compared to patients with TG values of ~440–800 mg/dL, underscoring the need to reduce TG in this population [7]. Long-term complications of FCS as a result of acute pancreatitis may include chronic pancreatitis, pancreatogenic (Type 3c) diabetes, and exocrine pancreatic insufficiency, with their attendant complications.