October 16, 2017Quiz
Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome and was featured in the 1992 movie Lorenzo's Oil. This devastating neurodegenerative disease typically affects young boys and causes death within 10 years. It is a result of fatty acid buildup caused by the relevant enzymes not functioning properly, which then causes damage to the myelin sheathes of the 1) ___, resulting in seizures and hyperactivity. Other side effects include problems with speaking, listening, and understanding verbal instructions. ALD is a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the 2) ___. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes.
Clinically, ALD is a heterogeneous disorder, presenting with several distinct phenotypes, and no clear pattern of genotype-phenotype correlation. As an X-linked disorder, ALD presents most commonly in males, however approximately 50% of heterozygote 3) ___ show some symptoms later in life. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. It is characterized by normal development in early 4) ___, followed by rapid degeneration to a vegetative state. The other forms of ALD vary in terms of onset and clinical severity, ranging from adrenal insufficiency to progressive paraparesis in early adulthood (this form of the disease is typically known as adrenomyeloneuropathy).
ALD is caused by mutations in ABCD1, a gene located on the X chromosome that codes for ALD, a peroxisomal membrane transporter protein. The exact mechanism of the pathogenesis of the various forms of ALD is not known. Biochemically, individuals with ALD show very high levels of unbranched, saturated, very long chain fatty acids, particularly cerotic acid. The level of cerotic 5) ___ in plasma does not correlate with clinical presentation. Treatment options for ALD are limited. Dietary treatment is with Lorenzo's oil. For the childhood cerebral form, stem 6) ___ transplant and gene therapy are options if the disease is detected early in the clinical course. Adrenal insufficiency in ALD patients can be successfully treated. ALD is the most common peroxisomal inborn error of metabolism, with an incidence estimated between 1:18,000 and 1:50,000. It does not have a significantly higher incidence in any specific ethnic groups.
In a recent clinical trial, a gene therapy to treat cerebral adrenoleukodystrophy (CALD) effectively stabilized the disease's progression in 88% of patients. According to the results, published in the New England Journal of Medicine, 15 of 17 patients had stable neurologic functioning more than two years on average after receiving the gene 7) ___, which was administered in a clinical trial sponsored by bluebird bio. It is one of the largest gene therapy trials targeting a single-gene disease to be published to date. Although we need to continue to follow the patients to determine the long-term outcome of the gene therapy, so far it has effectively arrested the progress of CALD in these young boys, says David A. Williams, MD, chief scientific officer and senior vice-president for research at Boston Children's Hospital and president of Dana-Farber/Boston Children's Cancer and Blood Disorders Center and the lead author of the study. This is a devastating disease, and we are all quite grateful that the patients and their families chose to participate in the trial. The treatment leverages bluebird bio's proprietary Lenti-D gene therapy to deliver the functional gene to patients' stem cells in the laboratory.
According to Williams, This treatment results from more than two decades of investment in basic 8) ___ therapy research by the NIH and others. Since it was first described 100 years ago, ALD has robbed the function of children who, up until the disease's onset, had been developing normally, says Florian Eichler, MD, co-lead author on the study. Eichel added that These are children who have been growing and thriving, and then suddenly, their parents witness this devastating decline that starts with personality changes and then progresses to motor problems and loss of their ability to walk and talk.
Until now, stem cell transplantation using cells donated by another person has been the only known effective therapy for CALD. Yet, its efficacy is drastically reduced if performed during later stages of neurodegeneration and usually works best with a disease-free matched sibling donor, which fewer than one-quarter of CALD patients have. To perform the gene therapy, clinicians first collect a patient's blood stem cells, which give rise to all mature 9) ___ cells. In a highly-specialized laboratory that contains a clean room for preparation of medicines, a viral vector is used to insert a correct version of the faulty gene into the patient's stem cells. Then, after the patient receives chemotherapy to make room for the genetically altered blood stem cells in the bone marrow, the cells are infused back into the patient's bloodstream. According to Eichler, In my clinic, the impact of this trial has been phenomenal. Boys without a donor match for stem-cell transplant were often passing away within a year or two of their diagnosis. Now, with early diagnosis and gene therapy, these boys are living longer and some are thriving enough to play sports and participate in other normal day-to-day activities.
At the latest follow-up, all patients who participated in the clinical trial were expressing functional ALD protein, which their bodies had been unable to produce prior to gene therapy. The trial is ongoing and has received regulatory approval to expand patient numbers. There are two great advantages to gene therapy according to Williams. The first is that patients don't have to wait to find a donor match. The second is that, because we use their own, gene-modified stem cells, there's no risk of graft-versus-host-disease and the patients do not require any 10) ___ drugs, which can have very significant, even fatal, side effects.
The ALD gene therapy trial is part of a robust and growing portfolio of pediatric gene therapy trials at Dana-Farber/Boston Children's that also includes clinical trials for X-linked severe combined immune deficiency (bubble boy disease), chronic granulomas disease, a recently completed trial in Wiskott-Aldrich Syndrome and the use of gene therapy to treat some types of childhood leukemia using CAR T cells. In addition, the Food and Drug Administration has just approved a ground-breaking study at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center for the use of gene therapy to cure sickle cell disease. Sources: Boston Children's Hospital; New England Journal of Medicine, 2017; DOI: 10.1056/NEJMoa1700554; Gene therapy halts progression of cerebral adrenoleukodystrophy in clinical trial: The devastating neurodegenerative disease typically affects young boys and causes death within 10 years. ScienceDaily, 4 October 2017; Wikipedia; nih.gov.
ANSWERS: 1) nerves; 2) body; 3) females; 4) childhood; 5) acid; 6) cell; 7) therapy; 8) gene; 9) blood; 10) immunosuppression