Gene therapy for Wiskott-Aldrich Syndrome cautiously encouraging first results

Gene therapy is one of the current challenges of the modern medicine. To be able to correct the genetic defect hereditary transmitted in the family or acquired during pregnancy (de novo mutation) theoretical would be the best treatment.

But the translation from theory to clinical application is sprinkled by many questions that require answers from laboratory research and, in particular, clinically proven responses.

Safety on short and long term related with manipulation of the genetic information is a major concern related with this new approach, as alternative to blood forming stem cells transplant from a healthy donor.  

The importance of this aspect has been highlighted once more by the follow up of the first clinical trial evaluating the gene therapy for Wiskott-Aldrich Syndrome.

The first gene therapy clinical trial which was conducted between 2006 and 2009, had included 10 patients with severe Wiskott-Aldrich Syndrome.

All of them were reinfused with their own blood forming (hematopoietic ) stem cells after prior correction of genetic mutation by using a viral vector.

Although 9 from 10 patients were engrafted with prior “treated own stem cells” and a sustained partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis were noticed, this treatment have been proved to not be safety.

The viral vector chosen by the medical research team to be used as “genetic correction tool” was associated with induction of new mutagenesis.

Due to activation of several proto-oncogenes 7 patients had presented typical symptoms and signs associated with acute leukemia. The onset of acute leukemia was noticed by patients in average at 3 years after treatment (from 488 days till 1813 days).

Therefore finding a new viral vector was a mandatory condition in order to proceed with the research associated with gene therapy for Wiskott-Aldrich Syndrome applied in patients.   

In April 2010 a new clinical trial was started, this time being used a self inactivating viral vector, considered to be more safety. 3 young children with a moderate form of Wiskott-Aldrich Syndrome (WAS) were treated.

They showed stable expressing of WAS protein in immune cells and improvements in terms of immune function, platelet count, and clinical score.  No mutation associated with blood cancer was observed after 20 to 32 months.

These encouraging results were followed by the report of the 2nd center study.

7 patients with age ranging from 0.8 to 15.5 years were enrolled at Great Ormond Street Hospital (London, England) and Necker Children’s Hospital (Paris, France) in an open-label study between December 2010 and January 2014.

All of them had severe thrombocytopenia, which led to severe bleeding episodes and eczema and associated recurrent skin infections. Some had experienced recurrent, severe infections requiring hospitalization, while 6 of them had autoimmune disease.

Daniel Bristol is one of the first teenager patients who agree to face the challenge but also, to undertake the risks of undergoing an experimental treatment.

He was diagnosed with this disease at the age of 2 years and required frequent medical care for the management of disease symptomatology. His burden was even harder since his older brother died as consequences of some complications associated with Wiskott-Aldrich Syndrome, of which he suffered too.

Since 2011, after reinjection of own “treated blood stem cells” prior harvested from his bone marrow Daniel has shown no more symptoms of the disease.

Daniel’s mother Sarah said:

“Since being around two, Daniel has been in an out of hospital, but now his skin has cleared up and so has his asthma. It means he can get on with his life now.”

Not only Daniel, but also other 5 treated patients showed significant clinical improvements at 4 years after the clinical trial was initiated. The average number of days spent in hospital from an average of 25 has drop to 0 in the following 2 years after treatment.

Regarding the encouraging results of this clinical trial Adrian Thrasher, Professor in Paediatric Immunology, at Great Ormond Street Hospital in London said:

“We are entering a new era where genetic treatments are entering mainstream medicine and offering hope to patients for whom conventional treatments don’t work well or are simply unavailable,”

“The work shows that this method is successful in patients who, in the past would have very little chance of survival without a well match bone marrow donor.

“It also excitingly demonstrates the potential for treatment of a large number of other diseases for which existing therapies are either unsatisfactory or unavailable."

Talking about the treatment which was developed by biotech company Genethon, Fulvio Mavilio, Chief Scientific Officer said:

“It is the first time that a gene therapy based on genetically modified stem cells is tested in an international clinical trial that shows a reproducible and robust therapeutic effect in different centers and different countries.”



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