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HypoAlphalipoproteinemia (“low HDL”), as a general term, has historically been defined clinically as an HDL-cholesterol (HDL-C) less than 40 mg/dL (1.0 mmol/L) in men, and less than 50 mg/dL (1.3 mmol/L) in women. A number of etiologies, often metabolic, can underlie a reduced circulating level of cholesterol in the HDL fraction, for example diabetes, Metabolic Syndrome, obesity, and lack of physical activity (thus called secondary hypoAlphalipoproteinemia). In a very small percentage of the population, particularly among patients with the very lowest HDL-C values, there are patients who have a genetic defect (thus called primary hypoalphalipoproteinemia) affecting either the constituent components of the pre-β particle, the process of pre-β particle synthesis, the steps leading to maturation into an alpha HDL particle, or the rates of catabolism – any of which alone or in combination can then result in an inherited condition of a very low circulating HDL particle number.

Familial Primary HypoAlphalipoproteinemia (FPHA) includes patients with a heritable genetic defect in one of the key genes involved in HDL particle production or maturation (apoA-I, ABCA-1, LCAT), which are individually very rare (prevalence: less than one in one million births in the homozygous form) but in both homozygous and heterozygous forms can act in an autosomal dominant manner to cause low apoA-I levels and low HDL particle numbers through either decreased production or increased clearance and premature destruction of HDL particles, and ultimately result in accelerated atherosclerosis from a single final common pathophysiology of impaired reverse lipid transport and accumulation of cholesterol throughout the body, in particular the vasculature. FPHA caused by homozygous ABCA-1 deficiency is also known as Tangier’s disease. FPHA patients are at high risk of cardiovascular disease as a consequence of having inherited a virtually absent endogenous RLT system. Because of the specific characteristics of the disease and very limited available therapeutic approaches, FPHA remains an unmet medical need and a life-threatening condition.

Interview with Professor Jean Ferrières ,
Cardiologist at the CHU Toulouse Rangueil

Very low levels of HDL-C and/or ApoA-I in the blood are due to mutations in genes’ coding for ApoA-I, or ABCA1 (ATP Binding Cassette transporter A1) or LCAT (Lecithin Cholesterol Acyl Transferase).  All those proteins play a key role in the HDL metabolism, respectively in the function, transport and maturation of HDL.

Very low levels or absence of HDL-C and ApoA-I are characteristic of HDL deficiency. This leads to accumulation of cholesterol in many tissues, and in particular in the vessel walls. Severity of symptoms in subjects with HDL deficiencies is determined by the degree of deficiency. They may present a cardiovascular disease earlier than the general population, often before age 50.

The treatment strategy is to reduce the risk of atherosclerosis, which is the main mechanism of increased morbidity and mortality.

Familial Primary Hypoalphalipoproteinemia (FPHA), also known as Familial HDL deficiencies, are rare genetic disorders.
FPHA is caused by a genetic defect in one of the genes responsible for HDL function, synthesis and maturation, and is associated with a very low number of high-density lipoprotein (HDL)-particles, also reflected in a very low plasma concentration of apolipoprotein A-I (apoA-I).
The disease is also generally associated with a positive family history of low HDL-cholesterol (HDL-C) or premature cardiovascular disease.
Mutations in the key HDL gene products like the ATP-binding cassette transporter A1 (ABCA1), apoA-I and lecithin: cholesterol acyltransferase (LCAT) result in low circulating levels of HDL particles in these patients and, as such, an absent or deficient reverse lipid transport (RLT) capacity which is insufficient to prevent the accumulation of cholesterol in the peripheral tissues and results in the development of premature cardiovascular disease.

  • 1- ABCA1 deficiency

    1. ABCA1 deficiency is one of the underlying causes of familial primary hypoalphalipoproteinemia (FPHA).

    Homozygous ABCA1 deficiency, also called Tangier disease, is characterized by severe plasma deficiency or an absence of HDL particles and apolipoprotein A-I (apoA-I) and by an accumulation of cholesterol in tissues throughout the body (Puntoni et al, 2012). Subjects with Tangier disease present large, yellow-orange tonsils and/or neuropathy. Other clinical features include hepatomegaly, splenomegaly, premature myocardial infarction or stroke, thrombocytopenia, anaemia, and corneal opacities.

    cerenis ABCA1 a cerenis ABCA1 b cerenis ABCA1 c
    A B C

    Figure 1: Clinical symptoms of ABCA1 deficiency (Tangier disease).

    A: Characteristic orange tonsils in a patient with Tangier disease (Puntoni et al, 2012), B: Blood erythrocytes with numerous stomatocytes, C:  Coronary artery with 75% stenosis at the crux and 95% stenosis in the mid portion (B and C from Sampietro et al, 2009).

    Heterozygous ABCA1 mutations span a range from no to severe cutaneous symptoms equalling the homozygous state, depending on the location/penetrance of the mutation(s) and its impact on HDL particle synthesis and thus the HDL particle number. Subjects with heterozygote ABCA1 mutations which result in impaired HDL particle synthesis and maturation have markedly-reduced HDL and apoA-I as well and are associated with increased carotid intimal thickening and coronary event rates due to cholesterol accumulation in the vasculature (Clee et al, 2000).
    The underlying etiology for all clinical phenotypes of ABCA1 deficiency is the imbalance in cholesterol metabolism. The major carriers for cholesterol in the blood are lipoproteins, including the low-density lipoprotein (or LDL) particles, and the high-density lipoprotein (or HDL) particles. In a healthy human body, there is a balance between the delivery and removal of cholesterol. The LDL particles deliver cholesterol to organs, where it can be used to produce hormones, maintain healthy cells, and be transformed into natural products that assist in the digestion of lipids. The HDL particles remove cholesterol from arteries and tissues to transport it back to the liver for storage, recycling, and elimination through a pathway called “reverse lipid transport (RLT)”.

    Atherosclerosis is thought to develop following an imbalance in which there is too much cholesterol delivery by LDL particles (therefore often called “bad cholesterol") relative to the amount of removal by HDL particles (better known as “good cholesterol”). In subjects with a high level of LDL or a low level of HDL, the imbalance results in more cholesterol being deposited in the arteries than being removed. This imbalance in homeostasis can also be exacerbated by, among other factors, age, gender, high blood pressure, smoking, diabetes, obesity, genetic factors, physical inactivity, vascular disease of the extremities or the brain, and the consumption of a high-fat diet. The excess cholesterol carried in the blood on LDL particles is deposited throughout the body but frequently ends up in the lining of arteries, especially those found in the heart. Repeated deposits of cholesterol can cause life-threatening complications such as vascular inflammation, plaque formation, and narrowed or blocked arteries. The blocking of these arteries can result in chest pain, heart attack and possibly death.

    As mentioned previously, the classical model of atherosclerosis describes an imbalance in the cholesterol delivery-removal homeostasis mechanism in which elevated levels of LDL-C result in increased delivery of cholesterol to the peripheral tissues in the setting of normal or modestly reduced HDL levels (in the setting of obesity and diabetes, for example); however, FPHA is a corollary of that classical mechanism, involving an imbalance in the cholesterol delivery-removal homeostasis mechanism in which inadequate levels of HDL particles result in reduced/absent elimination of cholesterol from the peripheral tissues, even in the setting of relatively “normal” LDL-C levels.  The key pathophysiological mechanism of FPHA is therefore that the genetically inadequate removal/elimination capacity of the defective HDL pathway is easily overwhelmed by even a relatively normal delivery of cholesterol by the LDL pathway, leading to a greater accumulation of cholesterol into plaque at any given LDL-C level compared to patients with normal HDL particle numbers. For example, Harchaoui et al, 2009 and El Harchaoui et al, 2007 reported that neutral faecal sterol excretion and faecal bile acid secretion was significantly lower in subjects with FPHA compared to healthy controls.  Ultra-low HDL and reduced RLT capacity from birth causes an accumulation of cholesterol in atherosclerotic plaque starting from an early age and the emergence of heart disease at a younger age than normal (Glueck et al, 1986).

    Treatment with CER-001 is expected to address the imbalance by providing additional HDL particles and reducing the amount of cholesterol accumulating in body tissues through the increased elimination of cholesterol from the body. Consequently, the symptoms associated with apoA-I deficiency, in particular atherosclerosis, are expected to be reduced. This expectation refers to both homozygous and functional heterozygous defects.

    Cerenis is particularly interested in homozygous deficiencies and those heterozygous variants which have a negative impact on the translation of the ABCA1 protein or which result in a dysfunctional ABCA1, all of which result in the unifying clinical phenotype of a deficiency in circulating apoA-I levels and the HDL particle number, key risk factors associated with accelerated atherosclerosis via reduced reverse transport of cholesterol out of the body.

  • 2- ApoA-I deficiency

    2.    Apolipoprotein A-I (apoA-I) deficiency is one of the underlying causes of familial primary hypoalphalipoproteinemia (FPHA).

    Homozygous apoA-I deficiency is characterized by severe plasma deficiency or an absence of apoA-I and HDL. Clinically, subjects with apoA-I deficiency present corneal opacities, xanthomas, and cardiovascular diseases caused by atherosclerosis. Less frequently, apoA-I deficiency may lead to neurosensory symptoms like hearing loss, systemic amyloidosis, or even hepatic or renal failure.

    Heterozygous apoA-I mutations span a range from no to severe symptoms equalling the homozygous state, depending on the location of the mutation(s). Subjects with heterozygote apoA-I mutations which result in impaired HDL particle synthesis and maturation have markedly reduced apoA-I and are associated with increased carotid intimal thickening and coronary event rates.

    The underlying aetiology for all clinical phenotypes of apoA-I deficiency is the imbalance in cholesterol metabolism. The major carriers for cholesterol in the blood are lipoproteins, including the low-density lipoprotein (or LDL) particles, and the high-density lipoprotein (or HDL) particles. In a healthy human body, there is a balance between the delivery and removal of cholesterol. The LDL particles deliver cholesterol to organs, where it can be used to produce hormones, maintain healthy cells, and be transformed into natural products. The HDL particles remove cholesterol from arteries and tissues to transport it back to the liver for storage, recycling, and elimination through a pathway called “reverse lipid transport (RLT)”.

    Atherosclerosis is thought to develop following an imbalance in which there is too much cholesterol delivery by LDL particles (therefore often called “bad cholesterol") or too little removal by HDL particles (better known as “good cholesterol”). In subjects with a high level of LDL or a low level of HDL, the imbalance results in more cholesterol being deposited in the arteries than being removed. This imbalance in homeostasis can also be exacerbated by, among other factors, age, gender, high blood pressure, smoking, diabetes, obesity, genetic factors, physical inactivity, vascular disease of the extremities or the brain, and the consumption of a high-fat diet. The excess cholesterol carried in the blood on LDL particles is deposited throughout the body but frequently ends up in the lining of arteries, especially those found in the heart. Repeated deposits of cholesterol can cause life-threatening complications such as vascular inflammation, plaque formation, and narrowed or blocked arteries. The blockage of these arteries can result in chest pain, heart attack and possibly death.

    As mentioned previously, the classical model of atherosclerosis describes an imbalance in the cholesterol delivery-removal homeostasis mechanism in which elevated levels of LDL-C result in increased delivery of cholesterol to the peripheral tissues in the setting of normal or modestly reduced HDL levels (in the setting of obesity and diabetes, for example); however, Familial Primary Hypoalphalipoproteinemia (FPHA) is a corollary of that classical mechanism, involving an imbalance in the cholesterol delivery-removal homeostasis mechanism in which inadequate levels of HDL particles result in reduced/absent elimination of cholesterol from the peripheral tissues, even in the setting of relatively “normal” LDL-C levels.  The key pathophysiological mechanism of FPHA is therefore that the genetically inadequate removal/elimination capacity of the defective HDL pathway is easily overwhelmed by even a relatively normal delivery of cholesterol by the LDL pathway, leading to a greater accumulation of cholesterol into plaque at any given LDL-C level compared to patients with normal HDL particle numbers.   For example, Harchaoui et al, 2009 and El Harchaoui et al, 2007 reported that neutral faecal sterol excretion and faecal bile acid secretion was significantly lower in subjects with FPHA compared to healthy controls.  Ultra-low HDL and reduced RLT capacity from birth causes an accumulation of cholesterol in atherosclerotic plaque starting from an early age and the emergence of heart disease at a younger age than normal (Glueck et al, 1986).

    Treatment with CER-001 is expected to address the imbalance by providing additional HDL particles and reducing the amount of cholesterol accumulating in body tissues through the increased elimination of cholesterol from the body. Consequently, the symptoms associated with apoA-I deficiency, in particular atherosclerosis, are expected to be reduced. This expectation refers to both homozygous and functional heterozygous defects.

    To date, there is no specific treatment addressing deficiencies in ApoA1, ABCA1 and LCAT. No authorisation has been granted for any products in these deficiencies.

  • 3 - Orphan Drug designations

    In August 2014, Cerenis was granted two orphan drug designations by the European Medicines Agency (EMA) to use CER001 for the treatment of HDL-deficient patients resulting from gene defects coding for apoAI and ABCA1

    An orphan designation (EU/3/12/1051) for the treatment of LCAT deficiency has been granted in October 2012, by the EMA to Alphacore Pharma Limited UK, for use of human recombinant LCAT. However the product is still in early development and very few subjects were given the product.

    The current therapeutic strategy to treat patients with FPHA is therefore very limited and includes diet controlling and an aggressive LDL-lowering therapy. There is no available treatment to allow a correction and normalization of the HDL particles number and function.
    LDL lowering therapies have shown that they can reduce cardiovascular events by ca. 30% in patients suffering from atherosclerosis; they are the standard recommended treatment to address cardiovascular risk.

    However, numerous patients carrying HDL deficiencies (FPHA) have normal LDL levels, because the underlying pathophysiological mechanism is related to a dysfunction of cholesterol elimination rather than an excess of cholesterol transported by the LDL.
    An intensive hypolipidemic treatment will have a limited effect though. As a result a high percentage of the residual cardiovascular risk can only be addressed by specific, chronic therapies targeting HDL and correcting HDL deficiencies.

    The therapeutic principle to treat FPHA, resulting from a dysfunction of the reverse lipid transport, is based on a replacement therapy composed of a bio-engineering human recombinant ApoA1-containing the pre-β HDL particle. The HDL therapy will restore cholesterol transport leading to cholesterol elimination accumulated in the vascular walls, through the RLT. As a result cardiovascular events will be reduced, as well as HDL deficiency symptoms.

 

 

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