Wednesday, 25 April 2012

Reaserchers Inch Closer to Curing Haemophilia B

The goal for the human body is to maintain homeostasis physically, mentally and genetically, and for haemophilia suffers, this is an everyday battle. Haemophilia is a genetically linked recessive disorder located on the X chromosome, making it more prone to male inheritance caused by their heterogametic sex chromosome set XY (2010 pp. 303-305) (refer to Figure 1). The disease is characterised by the absence of specific proteins, leading to frequent episodes of slow constant bleeding, and if left untreated, can progress to dangerous levels.

(Figure 1: Pedigree for woman who carries 
the recessive gene (r) for haemophilia
 B who has children with a non-haemophilic
 male. As can be seen, the son has one 
X chromosome, consequently inheriting the disorder.)

 A person can suffer from one of three forms of haemophilia, each specified by the absence of a particular clotting factor. When a person bleeds, twelve different of clotting factors are required to stabilise the wound, and in haemophilia B, appropriate levels of clotting factor nine (IX) required for healthy function is not produced (2010 pp. 303-305).  This strand forms 23% of all haemophilia cases, and is present in 1 of every 40,000 people (2010 pp. 303-305). Therefore, because of its commonality and capability to reaching dangerous proximities, it has become a priority for medical researchers to reduce the likelihood of this occurring, one method being somatic gene therapy. In the past decade, there have been over ten different clinical trials for haemophilia gene transfer, all of with two common goals: cut treatment costs and improve effectiveness. The most successful trial was achieved in late December, 2011.

Researchers from University College London and  St Jude Children’s Research Hospital in America teamed up to produce perhaps the greatest advance towards conquering Haemophilia B. Because suffers of the disease produce only 1% of the total amount of Factor IX required  for proper blood clotting function, researchers took six male sufferers and exposed them to  a new genetic therapeutic style which was achieved as follows:

“We infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human Factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe haemophilia B (FIX activity, <1% of normal values)” (2011, Para 2) (The New England Journal of Medicine 2011).
(Figure 2: Genetically engineered adenovirus-associated 
virus successfully producing protein required for
 Factor IX by attacking the target cell.)
 By engineering the adenovirus-associated virus, a virus which has been used in earlier clinical trials, researchers were able to attack specific liver cells with the genetic matter required to produce blood clotting protein Factor IX (Gallagher 2011) (refer to Figure 2). The six participants were placed in three categories of dosage retrospectively, high, medium and low, and were monitored over a sixteen month period where dosage level higher than typical treatment (Gallagher 2011). 

(Figure 3: Increased dosage in week 8 clearly accounts
 for Factor IX (FIX) pike 10 weeks after vector infusion.)
After the treatment period, all participants experienced increased levels of Factor IX production ranging from 2% to 12%, the highest changes recorded in Participants 5 and 6 (refer to Appendix A) who received high dosage of the virus  (The New England Journal of Medicine 2011). Likewise, the application of a distractor by the alteration of dosage level further demonstrated the success of treatment. For example, a peak recorded in Participant 4 at around week 10 was caused when dosage was increased (week 8), dramatically increasing Factor IX production (refer to Figure 3). Alanine transaminase (ALT) levels were also tracked in Participants 5 and 6 to prove this phenomenon. According to the National Library of Medicine, ALT enzyme levels increase when the liver experiences trauma. Thus, it can be assumed that when this occurred (e.g. week 10 in Participant 5), Factor IX levels dropped as liver cells required to produce the protein were damaged (refer to Appendix A) (U.S. National Library of Medicine 2012).

(Figure 4: In Participant 5, it is observed that as ALT level 
increases at around week 10, Factor IX (FIX) level 
decreases as a result of trauma)
According to Dr Amit Nathwani, a researcher from University College London, haemophilia sufferers who increase Factor IX production to 12% no longer require constant clinical treatment, an achievement produced by the experiment which greatly improved the lifestyles of all six participants (The New England Journal of Medicine 2011). The dosage consequently achieved appropriate expression of the required Factor IX gene level in the liver, successfully battling extreme cases of the disease on a therapeutic level. However, more studies into the method are a prerequisite for successful justification. The hope for future sufferers to reduce effects and combat the disease altogether is a possibility, but at this present moment, as stated by Chris James, Chief Executive of The Haemophilia Society:

“… We hope that this research will eventually result in the removal of the need for regular injections and significantly reduce painful bleeds and debilitating joint damage for those living with haemophilia” (2011, Para 28) (Gallagher 2011).

  1. 1 Gallagher, J 2011, Haemophilia Gene Therapy Shows Early Success, BBC News, viewed 11th-03-2012,
  2. The New England Journal of Medicine 2011, ‘Adenovirus- Associated Virus Vector- Mediated Gene Transfer in Hemophilia B’, The New England Journal of Medicine, vol. 366. 
  3. Al-Tubaikh, AT 2010, Internal Medicine: An Illustrated Radiological Guide, Springer- Heidelberg, New York.
  4. Kinsey, BK 2012, Family Health from A to Z, Marshall Cavendish Corporation, New York.U.S. National Library of Medicine 2012, ALT, viewed 18th-03-2012,

Written by: Sarahmay Mulholland (42906988)

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