About Sickle Cell Disease (SCD)

Sickle Cell Disease (SCD) is an orphan disease due to a single mutation at position six in the 147 residues amino-acid long beta-globin chain of hemoglobin, original glutamic acid being replaced by valine residue. Sickle Cell Anemia (SCA) is the common manifestation of SCD and the most frequent hemoglobinopathy in the world, affecting over 50 million people worldwide. It is estimated that 5% of the world population is affected by these hemoglobinopathies for which very few treatments are available. SCA is one of the most common blood disorders in the US and affects 2 in 1,000 African Americans. An estimated 100,000 and 115,000 patients suffer from SCD in the US and EU, respectively. 

SCA significantly impairs quality of life and shortens lifespan. While hemolytic anemia and frequent vaso-occlusive crises (VOCs) are the most frequent complications for patients suffering from SCA, these patients are also facing high comorbidities including but not restricted to sensitivity to infections, pulmonary hypertension (PH), stroke, osteonecrosis, retinopathy, priapism, leg ulcers, acute chest syndrome and glomerulopathy.

Sickle Red Blood Cells (RBCs) are very rigid and fragile. The loss of RBC deformability is considered to be the primary factor responsible for the vaso-occlusive events, severe hemolytic anemia and progressive organ damages in patients suffering from above mentioned diseases.

Cholesterol and Red Blood Cells (RBC)

RBC and myelin are the cell types with highest cholesterol phospholipid ratio. Noticeably, high concentration of cholesterol in RBC decreases its capacity to transport oxygen, thus detrimental and triggering the sickling process. Decreased high-density lipoprotein-cholesterol (HDL-C) level in SCD has been reported which may lead to an increased risk for endothelial dysfunction for patients suffering from this disease. This association could be related to the release of oxidized fatty acids during lipolysis, leading to endothelial cell inflammation.

Although sharing common mechanisms with atherosclerosis (oxidative stress, inflammation and vascular adhesion), SCA vasculopathy clearly differs in that cholesterol accumulation in arterial wall and atheroma have not been reported. Intriguingly, while plasma total lipids and cholesterols levels are usually lower in SCA than in healthy individuals, the level of total lipids and cholesterol is higher in the RBC membrane of SCA patients compared to healthy people which could be related to the decreased plasma Lecithin Cholesterol Acyl Transferase (LCAT) level found in SCD patients and more particularly during vaso-occlusive crises.

Patients with Sickle Cell Disease and Thalassemia have repeatedly been observed to display low HDL-C and low LDL-C plasma levels but increased oxidized LDL and plasma levels for the markers of oxidation. 

High-Density Lipoprotein (HDL) is central

The role of HDL in removing cholesterol from peripheral tissues such as macrophages is well established, in contrast to its potential role in removing excess cholesterol from RBC which has been and is still poorly investigated and thus offers very restricted therapeutic perspectives. RBC from SCD patients were observed to be significantly enriched in cholesterol as compared to heathy control subjects.

On the other hand, L-4F, an ApoA1 mimetic has been shown to improve vasodilation in hypercholesterolemia and in an animal model of Sickle Cell Disease but not in human clinical studies.

Role of antioxidants

Sickle cell disease, thalassemia, and glucose-6-phosphate-dehydrogenase deficiency are all hereditary disorders with higher potential for oxidative damage due to chronic redox imbalance in red cells that often results in clinical manifestation of mild to severe hemolysis in patients with these disorders. Decreased antioxidant level in both SCD and thalassemia are considered accelerated oxidative damage as one of the hallmarks in both SCD and thalassemia. More importantly, although dietary analyses suggest that dietary intakes of SCA individuals exceed the recommended daily allowances of all macro- and micronutrients (specifically, beta-carotene, alpha-carotene, and cryptoxanthin), carotenoids levels and more specifically, beta-carotene, alpha-carotene, and cryptoxanthin but also lycopene, lutein and retinol have been reported as markedly depressed when compared to those of healthy controls. These results suggest that in individuals with SCA, several micronutrients vital for maintaining the antioxidative capacities are present in lower quantities in plasma/serum. 

Moreover, vitamin E levels in plasma have been consistently found to be decreased in patients suffering from thalassemia.

The low level of plasma lipophilic antioxidant in SCD and thalassemia may enhance the pathological manifestations of increased oxidative stress well established in these diseases.

Technical Instrument for assessment of compound with anti-sicking activity

Laser Optical Rotational Red Cell Analyzer

Lorrca Maxsis osmoscan (Lorrca®) is a unique instrument which combines  Red Blood Cell (RBC) deformability by ektacytometry, osmoscan and aggregometry; all temperature controlled. It is capable of fully automated measurement and calculation of various phenomena of RBC’s by analysis of their rheological behavior. The technique accurately detects deformability as a function of shear stress, pre-hemolytic stability and aggregation of the RBC’s and is of added value for hematology analysis.

Possible measurements of the instrument
Evaluation of the rheology of blood in different parts of the body is a very specific task, therefore it is important to have a technique available that can accurately measure the RBC properties. Lorrca incorporates a variety of techniques to perform these specific measurements:

• Deformability: Laser diffraction ektacytometry, Parameterization of deformation curve, Cell- and cell membrane stability
• Osmoscan: Deformability under an osmotic gradient, Osmotic Resistance Test
• Aggregation & dis-aggregation: Syllectometry – Extent of aggregation, aggregation kinetics and tendency
• Oxygenscan; Measuring the relative oxygen pressure at the critical point the red blood cells start to sickle

For more information:

http://www.lorrca.com/

https://rrmechatronics.com/

HARTIS Pharma innovative strategy against SCD

HARTIS Pharma is a new biotech, founded by Eric Niesor (PhD) and his two associated co-founders Renée Benghozi (MD) and François Lamour (PhD). The company is located in Nyon, Switzerland and aims to reconsider the physiological role of HDL and specifically its key role in the regulation of cellular membrane as well as its essential activity in lipophilic antioxidant transport.

Despite SCD was identified more than a century ago, current few treatment options for the patients are still of limited efficacy and the disease is still a life-limiting and devastating condition then remaining a high unmet medical need. Considering RBC is the largest pool of cholesterol directly exchangeable with plasma lipoproteins and that SCD patients have i)high plasma membrane cholesterol concentration as well as increased oxidative stress, ii)decreased plasma HDL concentration and activity as well as iii)decreased oxygen transport by RBCs, HARTIS Pharma innovative therapeutic approaches aim at restoring RBC oxygen transport functions though High-Density Lipoprotein (HDL) excess cholesterol removal properties from RBC and antioxidant protective activity. Considering the new innovative mode of action of the clinical candidates from HARTIS Pharma portfolio, it is fairly conceivable that these new treatment approaches may benefit to SCD patients on top of any approved or currently under clinical development treatments.

HARTIS Pharma beyond SCD

In addition to SCD and Thalassemia, low HDL levels, high RBC membrane cholesterol, high blood viscosity and low blood levels of lipophilic antioxidants, are also observed in more common pathologies of the general population such as diabetes and cardiovascular diseases  and may be at the origin of diabetes complications.

Attempts to address simultaneously the common features linking these dysregulations affecting SCD, thalassemia and diabetes have not been made and vascular as well as microvascular complications of these diseases are still unmet medical needs.

Sickle Cell Trait (SCT) carriers are characterized by the presence of both non mutated hemoglobin (HbA) and mutated HbS (AS genotype) in their RBCs. Contrary to SCD only one abnormal hemoglobin gene is inherited. It is estimated that 300 million people worldwide are heterozygous for the HbS mutation. For several decades, SCT has been considered as benign with no clear and life threatening phenotype like SCD. HOWEVER, as early as 1963, vulnerability of SCT patients to high altitude has been reported and infection is nowadays established beyond doubt as more frequent in SCTs. In fact, apparent viscosity of SCT blood increases inversely to decrease of oxygen tension and may stop flowing under completely anoxic conditions. As of today, number of complications including but not restricted to splenic infarction at high altitude, with exercise, or with hypoxemia, hematuria secondary to renal papillary necrosis, fatal exertional heat illness with exercise, sudden idiopathic death with exercise, glaucoma or recurrent hyphema following a first episode of hyphema, bacteruria in women, bacteruria or pyelonephritis associated with pregnancy, renal medullary carcinoma in young people (ages 11 to 39 years), early onset of end stage renal disease from autosomal dominant polykystic kidney have been noticed as associated with SCT. Moreover, SCT with Type 2 Diabetes (T2D) have higher incidence of retinopathy, nephropathy and hypertension and it is suggested that SCT could exacerbate multiple factors that increase the risk of T2D-related vascular complications including arterial stiffness, blood hyperviscosity among others. SCT can therefore be recognized as a unique pathological profile different from SCD and it is clear that this population could benefit from orally bioavailable, low dose and safe therapy. HARTIS Pharma is currently investigating potential therapeutic approaches that could benefit to SCT patients.