Good Literature Review On Gene Therapy For Pediatric Adrenoleukodystrophy
Adrenoleukodystropy abbreviated as X-ALD is a serious genetic disorder that progressively affects the adrenal glands, the nervous system, and the spinal cord. The disorder was first identified in 1923 and was known as Schilder’s disease and later sudanophilic leukodystrophy. Dr. Michael Blaw renamed the disease to adrenoleukodystrophy in 1973. This was in recognition of the three main areas of the body that the disorder affects.
In this paper, we will examine various journals that cover the definition of the disease and its biochemistry. We will also examine the available approaches to treatment that patients are suffering from the condition have. Finally, we will highlight some of the ongoing research in the field of gene therapy for X-ALD and the possibility of future breakthroughs for patients. Recent research indicates that gene therapy holds the most promise in minimizing or halting the effects in patients with early onset ALD.
Launay et al(2015) defines Adrenoleukodystrophy (X-ALD) as a hereditary disease that results in impaired excessive storage of very long chain fatty acids (VLCFA) in the body’s tissues due to a loss of function of ABCD 1, the peroxisomal transporter. VLCFA lipids cause harm to cells and body tissues including the adrenal glands, brain, spinal cord, and testis (Launay et al, 2015). If left untreated, VLCFA-lipids eventually destroy the myelin sheath, which is the white matter that surrounds nerves, leading to serious neurological problems for sufferers. Another consequence of VLCFA-Lipids is Addison’s disease because the lipids are toxic to the adrenal glands leading to malfunctions (Launay et al, 2015).
Wood (2010) reckons that most of the VLCFA-Lipids found in the body are from the natural elongation of long-chain fatty acids within the cells, however, a small amount comes from diet. X-ALD patients accumulate VLCFA-lipids because they are unable to degrade the fatty acids that take place in the peroxisome cells. The patients either lack or have a defective ALDP (X-ALD) protein that is essential for the degradation of VLCFA to occur.
X-ALD patients have limited treatment options, however, gene therapy has emerged as one of the most promising treatments that may be fully available to ALD patients (Naldini, 2009). Gene therapy involves introducing corrected genetic sequences to form a new blueprint for affected cells (Naldini, 2009 & Stephenson, 2009). The repaired cells acquire the ability to produce the crucial ALD protein that is absent or defective in ALD patients. The overall consequence of gene therapy is moderate reversal or complete halting of the disease. Patients undergoing stem cell transplants from donor umbilical cord or bone marrow also show disease halting. However, gene therapy utilize the patient’s own stem cells. Autologous transplantation reduces the risk of rejection and other complications associated with donor transplants (Stephenson, 2009).
According to Shapiro and his team (2000), all patients undergo mutation of the X-ALD gene, limiting doctors’ ability to predict the clinical outcomes of the disorder for individual patients. Some end up with adrenal insufficiency also known as Addison’s disease. Other patients develop adrenomyeloneuropathy (AMN) which is the most prevalent clinical outcome (Matsumuto et al., 2003). Almost all male X-ALD patients between the ages of 20 to 30 years develop AMN. AMN patients experience progressive neurological disability leading to muscle stiffness, weak legs, impaired sphincter functioning, and impotence (Shapiro et al. 2000). AMN patients have a higher risk of developing cerebral demyelination, a debilitating form of X-ALD. Another clinical manifestation of X-ALD is cerebral-ALD that occurs in children, adolescents, and adults (Shapiro et al. 2000). CALD progresses rapidly and devastates the body more than the other phenotypes. In early childhood, the earliest symptom is a decline is school performance that is often mistakenly diagnosed as attention deficit hyperactivity disorder (ADHD) (Shapiro et al. 2000). As the disease progresses, the patient loses language skills, sight, and mobility and ends up paralyzed. Death occurs within 3 to 5 years of the onset of the clinical symptoms (Shapiro et al. 2000).
X-ALD patients are asymptomatic at birth (Stephenson, 2009). According to Naldini (2009), successful gene therapy depends on early and timely intervention. Researchers have spent time in trying to devise procedures for early detection to enhance intervention results (Stephenson, 2009). Kaga et al. (2009) studied eight asymptomatic boys with cerebral adrenoleukodystrophy (CALD). The researchers conducted several neuropsychological tests and compared the results with those of symptomatic patients. The tests included the hematopoietic stem cell transplantation treatment and the Wechsler Intelligence Scale tests among other neuropsychological tests. Kaga and his team concluded that follow-up neuropsychological tests were essential for early detection of the onset of ALD in previously asymptomatic boys. They observed that neuropsychological abnormalities preceded clinically and MRI appearance of CALD (Kaga et. al. 2009).
X-ALD and AMN are both diagnosed using blood tests designed to measure the volumes of VLCFA-lipids in the blood. The test is highly accurate for male test subjects and about 20% of females (Kaga et. al. 2009). Doctors conduct DNA blood tests to confirm the results for women who may be genetic carriers (Kaga et. al. 2009). The Kennedy Kriegler Institute developed a test that detected VLCFA in blood spots. The latest advancement in research is in newborn testing to enhance monitoring, early detection and intervention outcomes (Kaga et. al. 2009).
Patients suffering from X-ALD disorders have very limited treatment options. CALD patients can go through gene therapy or stem cell transplant as long as doctors detect the disease early. Lorenzo’s oil is also used for dietary treatments in patients. About 70% of male X-ALD patients require adrenal steroid replacement therapy for a life- saving treatment for adrenocortical insufficiency (Wirth, Parker& Ylä-Herttuala, 2013). This treatment has no effect on the neurological symptoms of the patient. There are no curative therapies for the majority of AMN patients for both sexes. Lorenzo’s oil is a combination of oleic acid triglyceride (GTO) and uric acid triglyceride (GTE) combined in the ratio of 4:1 is used as a form of dietary therapy. When administered orally in clinical trials, it normalized the levels of plasma in X-ALD patients within one month.
Allogeneic hematopoietic stem cell transplantation (HSCT) holds great promise for X-ALD patients with cerebral involvement detected at an early stage. Gene therapy also holds a lot of promise for X-ALD sufferers. Researchers hope that in the near future, doctors will be able to transplant genetically corrected autologous hematopoietic cells using lentiviral vectors as a viable therapeutic option (Kemp et al., 1998: Shapiro et al., 2000). Cartier et al. (2009) recorded very encouraging results from the first two test patients. Cartier and her team found that the cerebral demyelination of the two test patients declined at 14 to 16 months after infusion of the genetically corrected cells (Cartier et al., 2009). This clinical a clinical outcome is comparable to that recorded in allogeneic HSCT therapy. Thus, the team concluded that ALD patients can benefit immensely from hematopoietic stem cells delivered through lentiviral-mediated gene therapy.
The goals of existing X-ALD treatments is to reduce the levels of VLCFA in tissues. There are a number of components that are capable of reducing VLCFA levels in plasma, these are lovastatin and bezafibrate although bezafibrate was eventually dismissed for failing to reach adequate drug levels in patients to lower VLCFA in blood cells (Aschheim et al., 2009). Lovastatin causes small decreases in VLCFA levels in the plasma but not in white or red blood cells. The only hope for X-ALD patients in the future is in HSCT and gene therapy.
Aschheim, K., DeFrancesco, L., Hare, P., & Mak, C. (2009). Research highlights. Nature Biotechnology, 27(12),
Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., & l'Homme, B. (2009). Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy. Science, 326(5954), 818-823.
Kaga, M., Furushima, W., Inagaki, M., & Nakamura, M. (2009). Early neuropsychological signs of childhood adrenoleukodystrophy (ALD). Brain & Development, 31(7), 558-561.
Kemp, S., Wei, H., Lu, J., Braiterman, L. T., McGuinness, M. C., Moser, A. B., & Smith, K. D. (1998). Gene redundancy and pharmacological gene therapy: Implications for X- linked adrenoleukodystrophy. Nature Medicine, 4(11), 1261.
Launay, N., Aguado, C., Fourcade, S., Ruiz, M., Grau, L., Riera, J., & Pujol, A. (2015). Autophagy induction halts axonal degeneration in a mouse model of X- adrenoleukodystrophy. Acta Neuropathologica, 129(3), 399-415.
Matsumoto, T., Tsuru, A., Amamoto, N., Shimizu, T., Kondoh, T., Saitoh, N., & Tamagawa, K. (2003). Mutation analysis of the ALD gene in seven Japanese families with X-linked adrenoleukodystrophy. Journal Of Human Genetics, 48(3), 125.
Naldini, L. (2009). A Comeback for Gene Therapy. Science, 326(5954), 805-806.
Shapiro, E., Krivit, W., Lockman, L., Jambaque, I., Peters, C., Cowan, M., & Aubourg, P. (2000). Long-term effect of bone-marrow transplantation for child-onset cerebral X- linked adrenoleukodystrophy. Lancet, 356(9231), 713.
Stephenson, J. (2009). Gene Therapy and ADL. JAMA: Journal Of The American Medical Association, 302(23), 2531.
Weber, F. D., Weinhofer, I., Einwich, A., Forss-Petter, S., Muneer, Z., Maier, H., & Berger, J. (2014). Evaluation of Retinoids for Induction of the Redundant Gene ABCD2 as an Alternative Treatment Option in X-Linked Adrenoleukodystrophy. Plos ONE, 9(7), 1-9.
Wirth, T., Parker, N., & Ylä-Herttuala, S. (2013). History of gene therapy. Gene, 525(2), 162- 169.
Wood, H. B. (2010). Successful gene therapy in X-linked adrenoleukodystrophy. Nature Reviews Neurology, 6(1), 4.
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