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).

Sunday, November 29, 2009

A day of awareness and advocacy

1 December 2009: World AIDS Day

On Tuesday UNAIDS—a joint UN program which seeks to fight HIV/AIDS through the partnership of 10 different non-governmental programs—will remember those affected by HIV/AIDS; raise awareness about the effects of HIV/AIDS; advocate for increased HIV/AIDS research, treatment, and prevention; and celebrate their accomplishments in the battle against HIV/AIDS. According to the WHO, the purpose of World AIDS Day is to “draw[s] together people from around the world to raise awareness about HIV/AIDS and demonstrate international solidarity in the face of the pandemic.” After reading several personal accounts, posted on the World AIDS Campaign site, regarding the effects of HIV/AIDS, I could not help but post a response to my October 22 post relating to the continuance of HIV vaccine research.

On November 24 a news release was published by UNAIDS stating a 17% reduction in new HIV infections since 2001. As stated in the press release, HIV prevention programmes are making a difference!

· An estimated 33.4 million people are currently living with HIV worldwide. There were approximately 2.7million people newly infected in 2008. Additionally, an estimated 2million people died of an AIDS related illness in 2008

· A higher amount of HIV-infected people are currently living than ever before, due to the increased life-expectancies of HIV-infected individuals as a result of the benefits of antiretroviral therapy.

· The number of AIDS related deaths has declined by over 10% in the past 5 years, as treatments become more available worldwide

· HIV prevention programs are not commonly made available to married couples, individuals over the age of 25, or widowers and divorcees, in many countries. However, the highest population of HIV-infected individuals falls under one or more of those categories, in most countries.

This just goes to show how important and beneficial HIV/AIDS research is. In relation to the last bullet point, it is critical that HIV/AIDS research continues and that more HIV prevention programs are either established or expanded. In the words of Dr. Margaret Chan, Director General of WHO, “We cannot let this momentum wane. Now is the time to redouble our efforts, and save many more lives."

Saturday, November 28, 2009

An update on H1N1

According to this week’s HealthMap Blog Somalia reported its first cases of H1N1, raising the pandemic into 86 different nations. Furthermore, HealthMap reported on the emergence of Tamiflu-resistant strains among hospitalized patients in Wales. The BBC News reported, last Friday 20 November, that while the strain does not appear to cause more severe illness in patients than the common H1N1, and while this was expected by virologists and public health officials, its rise and even more so person-to-person transmission is of serious concern to public health. Additionally, similar cases were reported last Friday at the Duke University Hospital in North Carolina. Little more information was found regarding these cases; however, reports have stated that much ongoing research is investigating the detriment caused by this strain.

In addition to the rise of the tamiflu-resistant strain, HealthMap also noted the most recent detection, by Norwegian scientists, of a mutated viral strain potentially causing infection deeper into the airways leading to more severe disease. However, the same mutated strain was also observed in Finland, where at least 14 lives have been claimed out of the Nation’s near 5,900 reported cases, yet the strain was not found to cause more severe illness. According to the WHO, this same mutation has been observed in China, Japan, Mexico, Ukraine, and the United States without appearing to give rise to increased virulence.

As the “swine flu” or, to be politically correct, H1N1 continues to wage war against the strength of the human immune system, supplemented with anti-viral drugs, and the management of public health; we should not succumb to public fears. Despite the approximate 525,000 reported cases, the near 7,000 deaths caused by H1N1, and the eastward spread of the virus, its activity has significantly decreased in the United States, where cases run the highest.

Happy Thanksgiving

Wednesday, October 28, 2009

Thursday, October 22, 2009

Progress in the war against invisible killers

In 2000, world leaders met at the UN in New York, to set up some Millennium Development Goals (MDGs) to be fulfilled by 2015. These goals included plans to eradicate malaria, HIV/AIDS, and Tuberculosis (TB). Upon reconvening in 2008, the assembly realizes the latter two of the 3 goals unrealistic and unattainable by 2015.

Malaria Current Goals: The leaders still seek to cut cases by 75%, 2000—2015, and malaria-caused deaths to zero. Progresses: Insecticide-treated use of bed nets has tripled in 16 of 20 sub-Saharan African nations since 2000. Free Artemisinin-based combination therapy (ACT) distributed at all public health facilities in Zanzibar, Tanzania, has reduced novel cases reported by 70%. Genomes of three major mosquito vectors have been sequenced. RTS S vaccine is going into phase III trials across large areas of Africa. Problems: It has been estimated that $900 million more per year is required to develop vaccines and novel insecticides.

HIV/AIDS Current Goals: Universal access to HIV-AIDS treatment by 2010 Progresses: Rate of new infections fell from 3 million in 2001 to 2.7million in 2007. AIDS death rate dropped from 2.2 million in 2005 to 2 million in 2007. Approximately 3 million people living in low income nations are now receiving anti-retroviral treatments. World leaders pledged another $500 million to achieve goals. Problems: Demand for treatments far exceeds supply. Prevention is exceedingly difficult due to scientific, political, and cultural reasons.

TB Current Goals: Treat 50 million TB-infected people and prevent 14 million deaths Progresses: Incidence has slightly decreased. Global TB-prevalence rate fell by 2.8% and the corresponding death rate fell by 2.6%. Problems: TB detection is lagging, particularly in Africa, China, and India. Drug treatments are difficult to control.

Stone, M. 2009. Determined Progress in War against Malaria, HIV-AIDS, and TB. Microbe 4:115—118.

The cost-effectiveness of the continuance of HIV vaccine research

In recent years much scientific literature has reported the repeated failures of potential HIV vaccines to pass the phase II and phase III trials. In 2008 a potential vaccine, developed by Merck, failed its phase III trial, for the second time. As a result, the NIAID (National Institutes of Allergy and Infectious Diseases), among others, began to debate and reconsider the cost and benefit of HIV vaccine research and development. In 2007-2008 Elisa Long, Margaret Brandeau, and Douglas Owens conducted a study assessing “the outcomes for a broad range of vaccine efficacy and costs, and the outcomes associated with either universal vaccination or vaccination targeted to high-risk groups.”

Demographic information of currently reported HIV-positive individuals in the U.S, including behavioral patterns, was extrapolated using a set of differential equations to establish a model simulating the HIV epidemic over a 20 year period. This model depicts the proposed transmission and progression of HIV/AIDS and the cost-effectiveness for various vaccine strategies. They took into account several variables, such as the thought that antiretroviral therapy would decrease an individual’s infectivity thus possibly reducing transmission probability; however, increased life-expectancy of individuals would also increase measure of sexual activity and/or needle-sharing behaviors thus potentially increasing transmission.

They estimated that without any vaccine program in place, 1.29 million new HIV cases would occur over a 20 year period. They projected that a universal vaccination program, with a 75% efficacy and lifetime duration, would prevent 912,000 cases (71%) over the 20 year period, with 196 million individuals being vaccinated. A vaccination program targeting uninfected high-risk groups could result in 774,000 cases (60%) being prevented, with 9 million individuals being vaccinated. Finally, the less efficient strategy, by targeting low-risk individuals, 187 million individuals would require vaccination in order to return a reduction by 110,000 cases (12%). The model also suggests that for only a 5 to 10-year protection period, still with 75% efficacy, and universal vaccinations, approximate 420,000 — 610,000 cases can be prevented. Vaccinating high-risk groups would, obviously, greatly reduce the prevalence of HIV among those individuals, but could also significantly decrease the prevalence among low-risk individuals, due to reduced secondary transmission. The analysis appeared to suggest that with a high-risk exclusive vaccination program, 75% efficacy and lifetime protection, the cost-savings in healthcare expenditures would approximate $31 billion.

Targeted vaccination of high-risk groups appears by far more efficient than universal vaccinations. However the authors suggest that should an effective vaccine be developed, a universal vaccine strategy should still be utilized in order to ensure most, if not all, high-risk individuals participate. As the authors only appear to take into account the cost analysis of the hypothetical 20 year period, they fail to address the costs, towards vaccine research, accrued over the previous 20+ years, as well as the costs to amount over the next indefinite number of years until full vaccine development. While I cannot speak to the cost-benefit versus sunken-costs of this research over the last 20 years, the increase in life expectancy of those HIV positive in the U.S., and the reduced transmission rate appear to be significant enough to continue research in vaccine developments.

Long, E.F., M.L Brandeau, D.K. Owens. 2009. Potential population health outcomes and expenditures of HIV vaccination strategies in the United States. Vaccine 27:5402—5410.