AAV vector carrying TYMP gene

Gene therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) using a new orphan drug consisting of an adeno-associated virus vector carrying the TYMP gene. Phase I/II clinical trial.

Ramon Marti, Vall d'Hebron Research Institute (VHIR), Spain

29th March 2015

TACT reviewed an application from Dr Marti and his team from the Vall d’Hebron Research Institute (VHIR) who are developing an in vivo gene therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), TACT was asked to provide input in preclinical development and clinical trial design. Patients with MNGIE do not have enough thymidine phospohorylase and the abolition of the enzyme activity leads to accumulation of thymidine and deoxyuridine in body fluids and cells. The build-up of thymidine and deoxyuridine results in damage to mitochondrial DNA, which leads to a severe clinical phenotype that is fatal in more than 80% of patients before the age of 40 years.  Development of a gene therapy product is very well adapted to treat this very rare disease. This gene therapy consists of an AAV2/8 (a serotype already used clinically in human for haemophilia) vector carrying a liver restricted human TYMP expression cassette. The promoter used is liver specific. The TYMP gene is responsible for the production of the Thymidine Phosphorylase (TP). There are promising results in the preclinical studies already available but need to be confirmed in a larger pivotal study. The proposed clinical trial is very interesting but should be adapted in terms of future preclinical results especially for the primary outcome measure. It well integrates the specifics related to gene therapy products. The TACT recommended that the applicant works with the most experienced centers. A limited understanding of the natural history of the disease, because we are in the case of an ultra-rare disease, will be a challenge for the determination of the clinical efficacy. The TACT recommends that the applicant get in touch with the agencies to discuss the clinical development of this product. This gene therapy has been granted orphan drug designation in Europe (August 2014) and in USA (September 2014) for MNGIE.

12 Apr 2017