Gene therapy for rare diseases

What are rare diseases?

Rare diseases, also known as very infrequent diseases, are potentially fatal or chronic and degenerative. The number of people affected is five per 10,000. Most of these diseases are of genetic origin and over 50% of them affect children. Currently it is calculated that in the European Union there are between 5000 and 8000 different rare diseases suffered by between 6 and 8% of the population, that is, between 27 and 36 million people. In Spain over 3 million people are affected.

What do we research?

Our laboratory focuses on understanding the pathophysiology of some of these rare diseases and on developing new therapeutic strategies based on gene transference, which may offer solutions for these pathologies.

We are using AAV vectors to achieve the sustained correction of the gene deficiency in these genetic diseases. Simultaneously, we are working on the improvement of gene transference vehicles, as a result of a better knowledge of the vector at a molecular level, and on the design of protein expression systems to create more effective therapies.

Our priority research is into five of these diseases: Wilson’s Disease, Dravet Syndrome, hyperoxaluria, inherited intrahepatic cholestasis and urea cycle disorders. Besides, this research favors advances in the development of therapy for another 300 rare diseases.

Additionally, we are collaborating with other research programs in CIMA focusing on other rare diseases:

  • Hepatology: acute intermittent porphyria (AIP).
  • Neurosciences: Huntington’s Disease (HD) and amyotrophic lateral sclerosis (ALS).
  • Cell therapy: inherited muscular dystrophies.

Most recent advances

  • Development of a gene therapy treatment (vector design and analysis for effectivity and toxicity) for acute intermittent porphyria (AIP) used in a phase I clinical trial at the Clínica Universidad de Navarra. Some of the patients treated have shown a certain improvement which drives us to continue with the development of these advanced techniques.
  • Development of a therapeutic vector which corrects the origin and reverts the symptoms of Wilson’s disease in animal models.
  • Development of similar strategies for hyperoxaluria.

Diseases we research as a priority in our laboratory

  • Wilson’s Disease

    • Research group leader: Dr. Oihana Murillo.

    • What it is: Wilson’s disease is an inherited disorder with one case occurring per 30,000 people. It is caused by mutation of the ATP7B gene, responsible for metabolizing copper. This mutation causes copper to build up in the liver and, a posterori, in other tissues such as the brain, and may cause motor and psychiatric disorders, together with other complaints.

    • Objective: We have developed a therapeutic vector which corrects the origen and reverts the symptoms of this disease in animal models. Our objective is to confirm its therapeutic and pharmacological effectiveness and its tolerance in pre-clinical models in order to begin the large-scale production of the vector at the clinical level for its delivery to patients. 

  • Dravet Syndrome

    • Research group leader: Dr. Rubén Hernández.

    • What it is: Dravet Syndrome is a rare genetic disease with one case occurring per 20,000 people. It is one of the most severe congenital epilepsies. It causes very frequent convulsions, occasionally long-lasting, which do not respond well to conventional pharmacological treatment. These symptoms usually begin at around four months of age. Later, it causes neurological disorders and intellectual disability. In over 80% of cases the cause is a mutation in the SCN1A gene, which results in a reduction of a sodium channel in the neurons responsible for controlling the propagation of nerve stimuli in the brain. In most cases these are new mutations in the individual, with no previous family history...

    • Objective: This disease offers a major challenge due to the size and relative instability of the SCN1A gene, and the complexity of its functions in the brain. For this reason, the Gene Therapy and Neurosciences programs at CIMA, in close collaboration with the Pediatric Department of the Clínica Universidad de Navarra, have initiated a project to transfer the corrected gene to the neurons by using high-capacity adenoviral vectors and to control its expression as physiologically as possible. Currently we are in the development phase of these vectors and assessing the most suitable regulatory sequences. For testing in animal models we are implementing an advanced model of the disease in mice, developed by the Fundación Síndrome de Dravet.

  • Hyperoxaluria

    • Research group leader: Dr. Gloria González Aseguinolaza.

    • What it is: Type I primary hyperoxaluria (PH1) is a rare metabolic disease caused by mutations in the AGXT, which encodes AGT. The absence of AGT leads to the blockage of the glyoxylate detoxification route and, consequently, to the accumulation of oxalate crystals in the kidney. The patients present with serious renal damage and the only remedial treatment is a liver transplant, in addition to a kidney transplant in most cases.

    • Objective: In collaboration with the Dutch company uniQure and European clinical groups we are working on the optimization of a therapeutic vector for this disease with funding from the American Oxalosis and Hyperoxaluria Foundation (OHF). Additionally, in collaboration with the Cell Therapy groups at CIMA, the Universidad de La Laguna and CIEMAT, we are working on the development of gene correction strategies to treat the disease. 

  • Progressive inherited intrahepatic cholestasis

    • Research group leader: Dr. Cristian Smerdou.

    • What it is: The progressive inherited intrahepatic cholestasis are due to mutations in genes which provide information for the formation of transporter bile molecules or enzymes. The first symptoms of this disease appear in childhood with liver damage and high bilirubin levels. The progress of the disease leads to the development of serious liver pathologies such as cirrhosis or hepatocellular carcinoma. Most patients with severe forms of these diseases must receive a transplant as there is no remedial treatment.

    • Objective: As in Wilson’s disease, our objective is to correct and revert the symptoms of this rare liver disease in animal models by means of gene therapy. Currently we are developing a therapeutic vector while simultaneously characterizing the animal model of the disease. 

  • Urea cycle disorders

    • Research group leader: Dr. Rafael Aldabe.

    • What it is: The urea cycle is responsible for converting urea into ammonia, a highly toxic product generated by the body through protein metabolism. Urea cycle disorders are caused by inherited mutations of some of the components of the cycle. It occurs in one per 35,000 neonates. These mutations cause the accumulation of toxic products and a deficiency of some metabolites. The most severe manifestation of these disorders is seen neonatally and produces encephalopathy caused by the accumulation of ammonium, and can bring about death or irreversible neurological damage.

    • Objective: At present patients are treated by reducing the concentration of ammonia by restricting the ingestion of protein and using chemical compounds which promote its elimination through alternative metabolic routes. This treatment does not cure but halts or delays the symptoms of the disease, although there is always a risk of an increase in the ammonia concentration as a consequence of an infection or another source of stress.  The only treatment that is currently effective is a liver transplant.
      In animal models it has been shown that gene therapy, using adeno-associated viruses, may be an effective treatment to cure these diseases. However, there is a limit to carrying out treatment in the neonatal period as an elimination of the therapeutic vector of the liver exists. Our objective is the development of an effective therapeutic approach for this type of disorders based on gene therapy by avoiding the disappearance of the therapeutic vector so that it can be administered in the first days or weeks of the patient’s life, thus avoiding the pathological development of the disease as soon as possible. 

"Our laboratory is working on developing new treatments for liver diseases, based on gene transfer using one of the safest and most effective viral vectors currently in existence: the adeno-associated virus. In the next few years, we hope to obtain a clear clinical benefit in patients with rare diseases such as Wilson's disease and hyperoxaluria", Dra. Gloria González, Program Director.


Síndrome de Dravet


Cristina López
Avda. Pío XII, 55
31008 Pamplona

(+34) 948 194 700 Ext. 6021