Saturday, December 5, 2009

White Matter Matters... p.2

Adrenoleukodystrophy (ALD) is a neurodegenerative disorder, and although it is not an infectious disease, which is the focus of this blog, there has been some groundbreaking research recently published regarding this chronic illness that I am excited to write about.

Current Research: Due to the high risk of the bone marrow transplant (HCT) brought on to the patient and the occasional lack of donor match availability, recent research has focused on a means of gene therapy for treating ALD. On November 06, 2009, Science magazine published a research article regarding the successful development of a potential ALD therapy, and the so far successful treatment of two 7-year old males diagnosed with ALD and exhibiting progressive cerebral demyelination. Patient 1 contained a large deletion from exon 6 of the ABCD1 gene, while patient 2 contained a missense (E609K) mutation on ABCD1.

Peripheral blood mononuclear cells (PBMCs) were taken from the patients. Immunomagnetic separation was used to isolate the CD34+ cells. The stem cells were then infected with a replication-defective Lentiviral vector expressing wild type ABCD1 cDNA. The transduced cells were later transplanted back into the patients.

In patient 1, 23% of his PBMCs were observed to express ALD protein, and 25% of patient 2’s PBMCs were observed to express ALD protein 30 days after transplantation. Nine months after gene therapy expression levels dropped by approximately 10% in each patient. Thirty months after treatment, each patient’s ALD protein expression levels were found stabilized to 10% and 15% respectively in the PBMCs. Furthermore, 24 months after gene therapy very long-chain fatty acids were found to be reduced by 20% and 28% in each patient, respectively.

Brain MRI scans were taken of patient 1, patient 2, and an untreated ALD patient. An increase in demyelination was observed in all three patients between diagnosis and 12 months after gene therapy. However, scans of both 16 months and 24-30 months after gene therapy showed demyelination had leveled and stopped increasing. In the untreated patient, scans taken at 18 months and 24 months post-diagnosis each showed significant degradation in the brain and increasing demyelination. Most importantly here is the absence of actual brain tissue degradation, exhibited in bone marrow transplantation patients, along with the treated patients’ comparable cease of demyelintaion. While extensive testing still remains for this therapy, the fact that its results compare strongly to the positive results of the bone marrow transplant indicates a major success in research and the prospect for a new treatment.


Cartier, N., S Hacien-Bey-Abina, CC Bartholomae, G Veres, M Schmidt, I Kutschera, M Vidaud, U Abel, L Dal-Cortivo, L Caccavelli, N Mahlaoui, V Kiermer, D Mittelstaedt, C Bellesme, N Lahlou, F Lefrere, S Blanche, M Audit, E Payen, P Laboulch, B L’Homme, P Bougneres, C Von Kalle, A Fischer, M Cavazzana-Calvo, P aubourg. Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-linked Adrenoleukodystrophy. Science 326:818—823 (2009).

White Matter Matters... p.1

Adrenoleukodystrophy (ALD) is a neurodegenerative disorder, and although it is not an infectious disease, which is the focus of this blog, there has been some groundbreaking research recently published regarding this chronic illness that I am excited to write about.

Background information: ALD is an X-linked recessive disorder, indicating it is most commonly found among males and is inherited from the mother. It is characterized by an accumulation of very long-chain fatty acids in the brain, spinal cord, and plasma, which in turn destroy myelin sheath in the nervous tissue.

Very long-chain fatty acids are typically produced within the body and are transported into the peroxisome where they are broken down through β-oxidation. Myelin sheath is the white matter, or layer of lipid fats and proteins, “insulating” the axon of a nerve cell.

Figure 1: Very Long-Chain Fatty Acid Photo Credit: <>

The demyelination exhibited in ALD leads to vision loss, impaired coordination, difficulty swallowing, dementia, and paralysis. This illness is most commonly diagnosed at a young age and typically results in death within 2-4 years after diagnosis. At present, there is no general curative therapy for ALD. Traditionally, adrenal steroid replacement therapy and “Lorenzo’s Oil” has been used as treatment; however, both have little to no effect on neurological symptoms. A recent therapeutic method is hematopoietic cell transplantation (HCT), or in other words, bone marrow transplantation. HCT stops cerebral demyelination, thereby arresting the disease progression. Despite the apparent benefits to this treatment, this procedure puts the patient at a very high risk.

Figure 2: Brain MRI scans of 10-year-old, male, ALD patient Photo Credit: Tolar, et al. 2007

Figures 2, images A—D depict the MRI scans of an ALD patient, prior to HCT. Extensive inflammation and an abnormally high presence of white matter are observed in the various regions of the brain. Figures 2 E—H depict the MRI scans of the patient, 3 months after treatment. A significant decrease in white matter is observed; however, atrophy and deterioration of the actual brain tissue is also seen.

References: X-linked Adrenoleukodystrophy Database. Kennedy Krieger Institute, Human Genome variation Society, & Academic Medical Center University of Amsterdam. (last updated 19 Nov 2009, accessed Dec 2009)

Tolar J., P.J. Orchard, K.J. Bjoraker, R.S. Ziegler, E.G. Shapiro & L. Charnas. N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy. Bone Marrow Transplantation 39:211--215 (2007).