Dr. Luis Sendra Gisbert

Clinical Translation of Gene Therapy for AATD treatment: AAT gene implementation and edition by CRISPR/Cas9 in human liver segments

Deficiency in AAT (AATD) is a disease the gene therapy could cure in the near future. Gene addition is the most widely developed strategy in which I have more experience, mainly in the translation of hydrodynamic gene delivery procedure from mouse to pig liver. We developed a model of human liver gene delivery ‘ex vivo' with promising results. Recently, we have constructed the plasmid hAAT-flag, aiming to evaluate the relative expression efficacy of the endogenous (hAAT) vs exogenous (hAAT-flag) gene and the required proportion of cells transfected. However, gene edition of hAAT could be the best choice for AATD cure. CRISPR/Cas9 has resulted a safe efficient and cheap strategy for gene edition and it can be delivered as naked DNA to human liver by our procedure. Thus, we also propose to evaluate, the possibility of mediating insertion/deletion mutations and specific site repair of frequent mutation of hAAT gene by CRISPR/Cas9 on human liver.

Curriculum Vitae Dr. Luis Sendra Gisbert

I am graduate in pharmacy, PhD in Biomedicine and Pharmacy and mastered in both molecular pathology and pharmacology at University of Valencia (Spain) My PhD thesis focused on the translational process of nonviral liver gene therapy, from ‘in vivo' mouse and pig to ‘ex vivo' human liver segments, employing mainly the hAAT gene and evaluating the molecular decoding process. The results lead to different articles demonstrating the efficiency and feasibility of the technique and suggesting its potential clinical interest. I have also worked in the clinical translation of gene therapy employing other genes with clinical interest such as immunosuppressive interleukin-10.

The following are the published articles in which I participated:

  1. Frasson M, Sendra L, Miguel A, Herrero MJ, Montalvá E, López-Andújar R, Martínez-Pastor J, Martí-Bonmatí L, García-Granero E, Aliño SF. Hydrodynamic IL10 gene transfer in human colon: results from an "ex vivo" study with potential clinical application in Crohn's disease. Inflammatory Bowel Disease. 2017 Aug;23(8):1360-1370.
  2. Megías-Vericat JE, Montesinos P, Herrero MJ, Moscardó F, Bosó V, Rojas L, Martínez-Cuadrón D, Hervás D, Boluda B, García-Robles A, Rodríguez-Veiga R, Martín-Cerezuela M, Cervera J, Sendra L, Sanz J, Miguel A, Lorenzo I, Poveda JL, Sanz MÁ, Aliño SF. Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia. Leuk Lymphoma. 2017 May;58(5):1197-1206.
  3. Miguel A, Sendra L, Noé V, Ciudad CJ, Dasí F, Hervas D, Herrero MJ, Aliño SF. Silencing of Foxp3 enhances the antitumor efficacy of GM-CSF genetically modified tumor cell vaccine against B16 melanoma. Onco Targets Ther. 2017 Jan 23;10:503-514.
  4. Sendra Gisbert L, Miguel Matas A, Sabater Ortí L, Herrero MJ, Sabater Olivas L, Montalvá Orón EM, Frasson M, Abargues López R, López-Andújar R, García-Granero Ximénez E, Aliño Pellicer SF. Efficacy of hydrodynamic interleukin 10 gene transfer in human liver segments with interest in transplantation. Liver Transpl. 2017 Jan;23(1):50-62.
  5. Sendra L, Miguel A, Pérez-Enguix D, Herrero MJ, Montalvá E, García-Gimeno MA, Noguera I, Díaz A, Pérez J, Sanz P, López-Andújar R, Martí-Bonmatí L, Aliño SF. Studying Closed Hydrodynamic Models of "In Vivo" DNA Perfusion in Pig Liver for Gene Therapy Translation to Humans. PLoS One. 2016 Oct 3;11(10):e0163898.
  6. Sánchez-Lázaro I, Herrero MJ, Jordán-De Luna C, Bosó V, Almenar L, Rojas L, Martínez-Dolz L, Megías-Vericat JE, Sendra L, Miguel A, Poveda JL, Aliño SF. Association of SNPs with the efficacy and safety of immunosuppressant therapy after heart transplantation. Pharmacogenomics. 2015;16(9):971-9.
  7. Sendra L, Pérez D, Miguel A, Herrero MJ, Noguera I, Díaz A, Barettino D, Martí-Bonmatí L, Aliño SF. Human AAT gene transfer to pig liver improved by using a perfusion isolated organ endovascular procedure. Eur Radiol. 2016 Jan;26(1):95-102.
  8. Sendra L, Carreño O, Miguel A, Montalvá E, Herrero MJ, Orbis F, Noguera I, Barettino D, López-Andújar R, Aliño SF. Low RNA translation activit limits the efficacy of hydrodynamic gene transfer to pig liver in vivo. J Gene Med. 2014 Jul-Aug;16(7-8):179-92.
  9. Miguel A, Herrero MJ, Sendra L, Botella R, Diaz A, Algás R, Aliño SF. Antitumor cell-complex vaccines employing genetically modified tumor cells and fibroblasts. Toxins (Basel). 2014 Feb 19;6(2):636-49.
  10. Carreño O, Sendra L, Montalvá E, Miguel A, Orbis F, Herrero MJ, Noguera I, Aliño SF, Lopez-Andujar R. A surgical model for isolating the pig liver in vivo for gene therapy. Eur Surg Res. 2013;51(1-2):47-57.
  11. Miguel A, Herrero MJ, Sendra L, Botella R, Algás R, Sánchez M, Aliño SF. Comparative antitumor effect among GM-CSF, IL-12 and GM-CSF+IL-12 genetically modified tumor cell vaccines. Cancer Gene Ther. 2013 Oct;20(10):576-81.
  12. Miguel A, Herrero MJ, Sendra L, Botella R, Algás R, Sánchez M, Aliño SF. Comparative antitumor effect of preventive versus therapeutic vaccines employing B16 melanoma cells genetically modified to express GM-CSF and B7.2 in a murine model. Toxins (Basel). 2012 Oct 31;4(11):1058-81
  13. Herrero MJ, Sabater L, Guenechea G, Sendra L, Montilla AI, Abargues R, Navarro V, Aliño SF. DNA delivery to 'ex vivo' human liver segments. Gene Ther. 2012 May;19(5):504-12. 

Dr. Luis Sendra Gisbert
Instituto de Investigación Sanitaria La Fe
Avenida Fernando Abril Martorell, 106
46026, Valencia, Spain