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  • 04171 Validation of anatomical and brain perfusion dynamics in AIP non-human primate model using non-invasive MRI, and assessment of efficacy with hPBGD mRNA therapy

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Poster 6
04171 Validation of anatomical and brain perfusion dynamics in AIP non-human primate model using non-invasive MRI, and assessment of efficacy with hPBGD mRNA therapy
  1. Daniel Jericó1,
  2. Leyre García-Ruiz2,3,
  3. Verónica Aramendía-Vidaurreta2,3,
  4. Lei Jiang4,
  5. Karol M Córdoba1,
  6. Maite Aznarez2,3,
  7. Francesco Urigo1,
  8. Ana Sampedro1,
  9. Alberto Rico5,
  10. Iñigo Insausti2,
  11. Manuel Alegre6,
  12. Azucena Aldaz7,
  13. Carmen Unzu8,
  14. Jose Luis Lanciego5,
  15. María A Fernández-Seara2,3,
  16. Paolo GV Martini4,
  17. Matías A Ávila1,3,9,
  18. Antonio Fontanellas1,3,9
  1. 1Hepatology: PorphyriasandCarcinogenesis Lab. Solid Tumors Program, CIMA-University of Navarra (UNAV), Pamplona and CIBERehd, Spain
  2. 2Radiology Department, Clínica Universidad de Navarra (CUN), Pamplona, Spain
  3. 3Instituto de Investigación Sanitaria de Navarra (IdisNA), Spain
  4. 4Moderna Inc, Cambridge MA, USA
  5. 5Neurosciences Department, CIMA-UNAV, Pamplona and CIBERNed, Spain
  6. 6Department of Clinical Neurophysiology, CUN, Pamplona, Spain
  7. 7Service of Pharmacy, CUN, Pamplona, Spain
  8. 8Gene Therapy and Regulation of Gene Expression Program, CIMA-UNAV, Pamplona, Spain
  9. 9Cancer Center CUN, Pamplona, Spain

Abstract

A previous observational study (NCT02076763) reported that 7 out of 8 patients diagnosed with acute intermittent porphyria (AIP) and experiencing recurrent acute attacks showed significant enlargement of brain ventricles compared to healthy volunteers. Among them, 2 patients also showed reduced cerebral blood flow (CBF) during and acute episodes. Similarly, AIP mice demonstrated reduced CBF and developed chronic dilatation of cerebral ventricles compared to wild type controls, a condition worsened following acute attacks. However, overexpression of PBGD by means of gene therapy successfully alleviated both symptoms.

In this study, we evaluated alterations in CBF and cerebral ventricles volume in a clinically relevant Non-Human Primates (NHPs) model before and after induction of AIP, while comparing current (hemin and givosiran) and emerging (hPBGD mRNA) therapies using a 3T Magnetic Resonance Imaging (MRI) scanner (Magnetom Skyra, Siemens Healthcare, Germany) equipped with 32-channel head array coil.

Perfusion quantification was performed using custom MATLAB scripts (The MathWorks, Inc). MRI images and quantification revealed a reduction in CBF in AIP NHPs starting one month after AIP induction. This hypoperfusion persisted during acute attacks triggered by administration of porphyrinogenic drugs such as sulfamethoxazole and phenobarbital. Remarkably, increased PBGD expression in the liver achieved through multidose administration of hPBGD mRNA was the unique treatment capable of restoring baseline CBF levels.

Ventricular volumes in NHPs were obtained using AFNI (Analysis of Functional NeuroImages, https://afni.nimh.nih.gov/), with voxel counts converted to cubic centimeters. NHPs exhibited an increase in ventricular volume following the induction of porphyria and recurrence of acute attacks. Only multidose administration of hPBGD mRNA therapy showed potential to restore normal volume values.

In conclusion: MRI proved to be a non-invasive and safe medical imaging technique capable of validating anatomical changes and brain perfusion dynamics in AIP. Our findings support the safety and translatability potential of multiple systemic administration of hPBGD mRNA as a promising therapeutic approach for addressing ventricular enlargement and CBF alterations in AIP.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjgast-2024-ICPP.37

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