Treatment Of Adrenoleukodystrophy Research Articles

Adrenoleukodystrophy an Overview

Adrenoleukodystrophy (ALD) is a rare X-linked peroxisomal oxidation disease caused by mutations in ABCD1. It presents with various clinical manifestations, including cerebral ALD, myelopathy, and primary adrenal insufficiency. About 80% of ALD patients suffer from adrenal insufficiency, and cerebral ALD affects one-third of boys under twelve, progressing to total impairment and death without treatment. Hematopoietic stem cell transplantation (HSCT) is the only disease-modifying treatment for early-stage cerebral ALD, but it does not halt adrenal insufficiency progression and carries significant morbidity and mortality risks. A recent gene therapy clinical trial showed short-term MRI and neurological outcomes equivalent to past HSCT treatments without the adverse side effects. Additionally, over a dozen states have initiated newborn screening (NBS) for ALD, with the number expected to triple by 2020. Genetic testing of NBS-positive newborns has identified novel variations of unknown significance, raising questions about monitoring and treating preclinical or moderate adrenal insufficiency or cerebral involvement. This presents further opportunities for genetic characterization. The availability of matching donors, transplant centers, and specialists will impact prompt treatment for those diagnosed with ALD at birth. As NBS and gene therapy trials improve ALD's clinical management and prognosis, endocrine management of presymptomatic and subclinical adrenal insufficiency will become increasingly important.

The Pathogenesis of Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a rare, inherited disorder that affects the brain, spinal cord, and adrenal glands. It is caused by mutations in the ABCD1 gene, which provides instructions for making a protein called ABCD1, which is involved in the metabolism of very long-chain fatty acids (VLCFAs). In ALD, the body cannot properly break down and clear VLCFAs, which can lead to the accumulation of these fatty acids in the brain and other tissues. This accumulation can cause inflammation and damage to cells and tissues, leading to various symptoms. Symptoms of ALD may vary depending on the type of ALD and the severity of the condition. Common symptoms include neurological problems, such as difficulty walking, speaking, behavioral changes, and problems with the adrenal gland, such as adrenal insufficiency which is a condition in which the adrenal glands do not produce enough hormones. ALD is a progressive disorder, meaning symptoms may worsen over time if left untreated. Treatment for ALD typically involves medications and supportive care to manage symptoms and prevent complications. Sometimes, a bone marrow transplant may be recommended to replace damaged cells and tissues.
 Genetic testing is available for ALD and can be used to diagnose the disorder and identify people at risk of developing it. Early diagnosis and treatment can help improve the chances of a full recovery and a good quality of life for people with ALD.

Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1.

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.

N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy.

The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N-acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1–100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.

In vivo gene editing via homology-independent targeted integration for adrenoleukodystrophy treatment

Adrenoleukodystrophy (ALD) is caused by various pathogenic mutations in the X-linked ABCD1 gene, which lead to metabolically abnormal accumulations of very long-chain fatty acids in many organs. However, curative treatment of ALD has not yet been achieved. To treat ALD, we applied two different gene-editing strategies, base editing and homology-independent targeted integration (HITI), in ALD patient-derived fibroblasts. Next, we performed invivo HITI-mediated gene editing using AAV9 vectors delivered via intravenous administration in the ALD model mice. We found that the ABCD1 mRNA level was significantly increased in HITI-treated mice, and the plasma levels of C24:0-LysoPC (lysophosphatidylcholine) and C26:0-LysoPC, sensitive diagnostic markers for ALD, were significantly reduced. These results suggest that HITI-mediated mutant gene rescue could be a promising therapeutic strategy for human ALD treatment.

New genome editing technologies in the treatment of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy is a severe progressive neurological disease that is predominantly found in male patients and caused by mutations in the X-linked ABCD1 gene encoding peroxisome transport protein. The disease is clinically characterized by two main phenotypes: the most severe infant cerebral form and adrenomyeloneuropathy. The disease is treated by allogeneic transplantation of hematopoietic cells from a healthy donor to stop progression, and gene therapy with a self-activating lentiviral vector, the carrier of the functional gene ABCD1. Each method has its own limitations. The authors present and theoretically substantiate an alternative approach to the treatment of adrenoleukodystrophy; they propose to modify the autologous CD34+ cells from the patient using genomic editing, in order to replace the mutant DNA sequence of ABCD1 gene with a wild-type sequence, while replacing the mutant protein in the edited cells. The edited autologous CD34+ cells can be introduced by their transplantation into the bone marrow or by a series of repeated intravenous infusions. This method will allow avoiding both the search for a donor and the graft-versus-host reaction

Orphan designation: Autologous haematopoietic stem cells transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA, Treatment of adrenoleukodystrophy

Orphan designation: Autologous haematopoietic stem cells transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA, Treatment of adrenoleukodystrophy

Orphan designation: Autologous haematopoietic stem cells transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA, Treatment of adrenoleukodystrophy

Orphan designation: Autologous haematopoietic stem cells transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA, Treatment of adrenoleukodystrophy

Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease that is caused by mutations in the ABCD1 gene and characterized by elevated levels of very long-chain fatty acids (VLCFA) in plasma and tissues, with the most pronounced increase in the central nervous system. Virtually all male patients develop adrenal insufficiency and myelopathy (adrenomyeloneuropathy), but a subset develops a fatal cerebral demyelinating disease (known as cerebral ALD). Female patients may also develop myelopathy, but adrenal insufficiency or leukodystrophy are very rare. ALD has been associated with mitochondrial dysfunction, oxidative stress and bioenergetic failure, but the mechanism by which VLCFA accumulation triggers these effects has not been resolved thus far. In this study, we used primary human fibroblasts from normal subjects and ALD patients to investigate whether VLCFA can induce endoplasmic reticulum stress. We show that saturated VLCFA (C26:0) induce endoplasmic reticulum stress in fibroblasts from ALD patients, but not in controls. Furthermore, there is a clear correlation between the chain-length of the fatty acid and the induction of endoplasmic reticulum stress. Exposure of ALD fibroblasts to C26:0, resulted in increased expression of additional endoplasmic reticulum stress markers (EDEM1, GADD34 and CHOP) and in lipoapoptosis. This new insight into the underlying mechanism of VLCFA-induced toxicity is of great importance for the development of a disease modifying treatment for ALD aimed at the normalization of VLCFA levels in tissues.

Combined transplantation of neural precursor cells and olfactory ensheathing cells for the treatment of X-linked adrenoleukodystrophy in children

Combined transplantation of neural precursor cells and olfactory ensheathing cells for the treatment of X-linked adrenoleukodystrophy in children Hui Yang,1,* Yu Zhang,1,* Zhaoyan Wang,1 Wei Lu,1 Fang Liu,1 Xin Yu,2 Xiaoyan Zheng,1 Yinxiang Yang,1 Zuo Luan,1 Suqing Qu1 1Department of Pediatrics, 2Department of Neurological Surgery, Navy General Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work. Abstract: Hematopoietic stem cell transplantation is only suitable for early-stage adrenoleukodystrophy (ALD). In this study, we observed the therapeutic efficacy of combined transplantation of neural precursor cells (NPCs) and olfactory ensheathing cells (OECs) on late-stage X-linked ALD in nine children who were admitted in our hospital between June 2009 and January 2014. Related patient information included onset time 3 months to 1 year, magnetic resonance imaging (MRI) score 11.02±0.90, and neurologic function score 2–3. All patients received combined transplantation of NPCs and OECs by injection around the lateral angle of the frontotemporal–occipital lesion under MRI guidance. It was found that the visual function, sleep, and communication obstacles were improved significantly without evidence of disease progression in six (66.7%) of the nine patients within 1 month after transplantation. In two of the six patients, the lesions became significantly smaller than before, although their MRI scores remained unchanged significantly. In addition, cell therapy did not induce any irreversible adverse event during the study period, indicating that combined transplantation of NPCs and OECs was safe and reliable, and could improve the clinical manifestations of ALD in children within a short time. Although this cell therapy was not able to halt the progression of the disease 1–3 months after transplantation, it could still be used as an early treatment and provide patients with more opportunities for hematopoietic stem cell transplantation, which is the only effective long-term treatment for X-linked ALD at present. The preliminary results from this study suggest that a comprehensive prevention strategy of serial and combined transplantation may improve some functions for ALD patients in the short-term, however, long-term effects need further study. Keywords: X-linked adrenoleukodystrophy, combined transplantation, neural precursor cells, olfactory ensheathing cells

P08.03 Erucic acid, a component of Lorenzo’s oil used in treatment of adrenoleukodystrophy, acts antineoplastic in C6 glioma cell culture

P08.03 Erucic acid, a component of Lorenzo’s oil used in treatment of adrenoleukodystrophy, acts antineoplastic in C6 glioma cell culture

Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history.

X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. Virtually all men with ALD develop adrenal insufficiency and myelopathy. Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). However, one cannot identify these individuals until the early changes are seen using brain imaging. Women with ALD also develop myelopathy, but generally at a later age than men and adrenal insufficiency or cerebral ALD are very rare. Owing to the multisystem symptomatology of the disease, patients can be assessed by the paediatrician, general practitioner, endocrinologist or a neurologist. This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies. Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.

Fresh from the designation pipeline: orphan drugs recently designated in the European Union (December 2013-February 2014)

Introduction: In this issue, designations for hypoparathyroidism, Farber disease, dengue, Rett syndrome, adrenoleukodystrophy, necrotizing enterocolitis, Alagille syndrome, Dravet syndrome, familial intrahepatic cholestasis, familial chylomicronemia, myotonic dystrophy and epidermolysis bullosa are discussed.Areas covered: Orphan drugs designated between December 2013 and February 2014 within the European Union are covered.Expert opinion: Pioglitazone, which was recently designated for treatment of adrenoleukodystrophy, is an example of a drug in which the advantages of the already known pharmacodynamics and preclinical efficacy can be speculated to speed up its development as an orphan drug.

부신백질이영양증 환자의 전신마취 하 치과 치료 : 증례보고

Adrenoleukodystrophy (ALD) is a rare, inherited disorder that leads to progressive brain damage and failure of the adrenal glands. It is passed down from parents to their children as an X-linked genetic trait. Therefore, it affects primarily males especially under the age of 10. People with ALD have excessive accumulation of very long chain fatty acids (VLCFAs) in their brain because they do not have the enzyme which break down these fatty acids. Special method for treatment of ALD is not available. Eating a diet low in VLCFAs and taking special oils, called Lorenzo's oil, can lower the blood levels of VLCFAs. But this oil cannot stop the destruction of nerve cell. This article presents a case report: Dental treatment of a 11-year-old male patient with ALD under general anesthesia. Careful management must be required during treatment procedure because of difficulty in cooperation, seizure disorders, gastroesophageal reflux, pulmonary aspiration and airway complications.

7. Neurological Internal Medicine in the EBM Era - Recent Progress in Treatment of Adrenoleukodystrophy

7. Neurological Internal Medicine in the EBM Era - Recent Progress in Treatment of Adrenoleukodystrophy

Lorenzo’s Oil in Treatment of Asymptomatic ALD

The effect of 4:1 glyceryl trioleate-glyceryl trierucate (Lorenzo’s oil) on disease progression in 89 asymptomatic boys (mean age 4.7+/-4.1 years; range 0.2-15 years) with X-linked adrenoleukodystrophy (ALD) and normal brain MRI was studied at Johns Hopkins University, Baltimore, MD, and other centers.

Natural history of X-linked adrenoleukodystrophy in Japan

The natural history of X-linked adrenoleukodystrophy (ALD) was investigated, using a nation-wide retrospective study based on a questionnaire survey. The data on 145 patients, including 46 patients with the childhood cerebral form, 39 with adrenomyeloneuropathy (AMN), 33 with the adult cerebral form, 14 with the adolescent form and 13 with the olivo-ponto-cerebellar (OPC) form, were analyzed. Initial symptoms of the childhood cerebral form were intellectual ( n=16) and visual ( n=11) disturbances, whereas those of AMN were gait ( n=37) and sensory ( n=3) disturbances; the adult cerebral form, psychic ( n=19) and gait ( n=11) disturbances; the adolescent form, visual n=5) and gait ( n=4) disturbances; and the OPC form, gait ( n=9) disturbance. Patients with onset under the age of 8 years progressed more rapidly than those over 8 years old. Visual, hearing, gait and swallowing disturbances progressed more slowly in the older group. About half of AMN patients showed cerebral involvement about 10 years after onset. Patients with the OPC form also showed a similar progression. A Kaplan–Meier plot clarified the characteristic pattern of progression of neurological symptoms in each phenotype. These finding will improve the understanding of the natural history of X-linked ALD and will provide a basis for the evaluation of specific treatment for X-linked ALD.

Adrenoleukodystrophy: The Restoration of Peroxisomal β-Oxidaton by Transfection of Normal cDNA

In order to elucidate the function of ALDP [a protein encoded by the gene responsible for adrenoleukodystrophy (ALD)], normal ALDP cDNA, inserted in an expression vector driven by chicken β-actin promotor, was transfected into ALE fibroblasts. In a transient expression system, the fatty acid composition did not change even though the ALDP was newly synthesized based on the findings of a western blot analysis. In a stable expression system, 3 cell lines were strongly positive for ALDP. In these cells the level of very long chain fatty acid (C26:0) turned out to be as low as those of the control, while the activities of C24 β-oxidation, as checked by two different methods, became normal. From these results, it is concluded that ALDP is indispensable for the function of peroxisomal β-oxidation, and thus the treatment of ALD may be possible by the supplementation of ALDP.

Purification of erucic acid by preparative high-performance liquid chromatography and crystallization

Eurucic acid (C22:1 fatty acid) has been found to be useful in the treatment of adrenoleukodystrophy (ALD). It appears to work by reducing the blood levels of very-long-chain fatty acids (VLCFAs) which destroy the myelin sheaths of the nerves. Erucic acid was purified by reversed-phase high-performance liquid chromatography (HPLC) on columns packed with YMC C 18 (10-20 μm, 120 Å). Using ethanol-water as the mobile phase, the recovery of erucic acid was 69% and the purity was more than 97% as measured by gas chromatography. The amount of saturated VLCFAs was found to be within the limits specified for ALD treatment. The production rate (yield per 8 h shift) was low, however. Using methanol-water instead of ethanol-water as the mobile phase, a ninefold increase in the production rate was achieved. The recovery of erucic acid was 65% and the purity of erucic acid was 98%. All other purity specifications were met. By performing a low-temperature crystallization after the preparative HPLC step, the production rate was increased a further 142%. This represents a 22-fold increase in production rate over the ethanol-water method. The crystalline erucic acid was found to be 99% pure. All other purity requirements were met. The yield for the combined process (HPLC plus crystallization) decreased to 55%, however.