Tuesday, December 27, 2011

A New and Promising Approach to the Treatment of Sickle Cell Disease

Sickle Cell Disease (SCD) is a serious genetic ailment that Impacts many individuals.  A patient with sickle cell anemia presents the following symptoms often beginning at 4 months old:

  • Painful episodes that can last hours or days
  • Attacks of abdominal pain
  • Bone pain
  • Breathlessness
  • Delayed growth and puberty
  • Fatigue
  • Fever
  • Jaundice
  • Paleness
  • Rapid heart rate
  • Ulcers on the lower legs (in adolescents and adults).

Other symptoms include:

  • Chest pain
  • Excessive thirst
  • Frequent urination
  • Painful and prolonged erection (priapism - occurs in 10 - 40% of men with the disease)
  • Poor eyesight/blindness
  • Strokes
  • Skin ulcers.

This disease was thought to have a genetic etiology based upon the epidemiological data which showed its prevalence among individuals of African descent (one in twelve African Americans are heterozygous for this trait).  Furthermore, these data also pointed to a recessive trait i.e. both alleles have to possess the altered gene for the symptoms to appear.

The disease presents with a singular characteristic – misshapen red blood cells.  This change in morphology from the normal disc-shaped cell to crescent-shaped is a direct result of the altered tertiary structure of the hemoglobin molecule (referred to as Hemoglobin S).  Normal hemoglobin has a globular - nearly spherical - structure.

In the past, this type of illness has been impervious to the possibility of a cure, since its origin resides in the very makeup of an individual's heredity as expressed through the genes.  Recent advances in molecular biology and gene therapy have demonstrated that this daunting limitation may be effectively breached.   For examples severe combined immunodeficiency (SCID) is a particularly devastating and ultimately fatal disease in which the affected child has no defense against infections.   Through the ground breaking work of Dr. Alessandro Aiuti, ten patients suffering from SCID are still alive.  The mutated gene in this condition is the ADA gene.   The laboratory of Dr. Aiuti from the San Raffaele Institute for Gene Therapy in Milan, Italy successfully used the following procedure: bone marrow cells from the patients involved were incubated with a specially engineered virus containing the normal ADA gene.  These engineered cells were reintroduced into the patients.  Positive results were seen almost immediately following treatment.   A similar approach has been used in the treatment of a disease characterized by a congenital degeneration of the retina.  In this study four of six patients had a notable improvement of vision.

In addition, a new methodology in the approach to improving the health of individuals with SCD is being developed by Doctor Jian Xu and his colleagues from the Division of Hematology/Oncology at Children's Hospital, Boston.   This discovery is linked to the fact that in humans, there is a switch from a fetal form of hemoglobin (HBF) to the adult form.  It has been previously demonstrated that the persistence of HBF in adults lessens the severity of SCD.  Furthermore the silencing of HBF is under genetic control.

Xu and his team, working with the mouse as the preferred animal model, have shown the loss of a transcription factor – BCL11A – reverses HBF silencing and, therefore, substantially lessens the severity of SCD.  Although there are currently substantial barriers to translating these findings into therapies for this disease, this discovery offers new possibilities for real progress in this regard. 

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