Autologous Mitochondrial Transplant for Cerebral Ischemia

Official title

Study Title: Autologous Mitochondrial Transplant for Cerebral Ischemia

Overview

The investigators propose to infuse healthy autologous mitochondria into cerebral vessels supplying brain tissue experiencing ischemia in patients who undergo standard-of- care endovascular reperfusion therapy.

Detailed description

Stroke is one of the leading causes of morbidity and mortality worldwide. More than 80% of strokes are the result of ischemia caused by blockage of one or more cerebral arteries. Lack of blood supply starves brain cells of necessary glucose and oxygen, and disturbs cellular homeostasis, eventually resulting in neuronal death.

Mitochondria are tiny organelles present in nearly all types of human cells and are vital to our survival. Much like a battery, they generate most of our adenosine triphosphate (ATP), the energy currency of the cell. Mitochondria are also involved in other tasks, such as signaling between cells and cell death. All these functions can be impaired during ischemia because of the damage caused to mitochondria.

Based on many preclinical studies in animals, damage caused by ischemia can be reversed after infusing healthy mitochondria into injured tissues. An ongoing clinical trial in human hearts at Boston Children's Hospital has also demonstrated that transplanting autologous mitochondria via infusion or direct injection is well-tolerated and safe.

The investigators at the University of Washington are recruiting subjects for a first-in-human-brain trial to confirm the safety of autologous mitochondrial transplant during brain ischemia. The transplantation will be performed within the same procedure as the clinically indicated reperfusion treatment.

During standard-of-care endovascular treatment for cerebral ischemia, the investigators will obtain a very small biopsy from the muscle tissue adjacent to our surgical access site. Muscle tissue will be processed at bedside to extract the autologous mitochondria as performed in prior human cardiac trial and validated in animal studies. The endovascular treatment proceeds without disruption as clinically indicated, and the mitochondria are infused into the brain artery via micro-catheter during reperfusion.

Interventions

• Other Endovascular autologous mitochondrial transplantation
  During standard-of-care endovascular reperfusion procedure, subjects will have autologous mitochondria infused via microcatheter into ischemic brain.

Primary outcome measures

• Incidence of severe adverse events during mitochondrial infusion [Time frame: Through completion of reperfusion therapy, up to one hour post-infusion]
• Incidence of severe adverse vascular events immediately post-mitochondrial infusion [Time frame: Up to 3 hours post-mitochondrial infusion]
• Incidence of severe systemic adverse events associated with mitochondrial infusion [Time frame: Up to seven days after procedure completion]
• Incidence of severe adverse events related to muscle biopsy [Time frame: Up to six hours after procedure completion]

Secondary outcome measures (1)

• Reduction of infarct volume post-mitochondrial infusion [Time frame: Up to seven days after procedure completion.]

Eligibility criteria

Inclusion criteria

• Eligible for endovascular thrombectomy to treat acute large vessel occlusion
• Eligible for angioplasty (microcatheter-based balloon/mechanical and chemical angioplasty) to treat acute cerebral vasospasm after aneurysmal subarachnoid hemorrhage
• Subjects for whom there is likely to be enough time to obtain meaningful consent from patient or legally-authorized representative

Exclusion criteria

• Unable to receive a brain MRI scan
• Known mitochondrial disease
• Hemodynamically unstable patients in whom standard of care endovascular reperfusion treatment cannot safely be performed or completed

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Harborview Medical Center — Seattle

Publications

• Preble JM, Pacak CA, Kondo H, MacKay AA, Cowan DB, McCully JD. Rapid isolation and purification of mitochondria for transplantation by tissue dissociation and differential filtration. J Vis Exp. 2014 Sep 6;(91):e51682. doi: 10.3791/51682. PMID 25225817
• Guariento A, Piekarski BL, Doulamis IP, Blitzer D, Ferraro AM, Harrild DM, Zurakowski D, Del Nido PJ, McCully JD, Emani SM. Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2021 Sep;162(3):992-1001. doi: 10.1016/j.jtcvs.2020.10.151. Epub 2020 Dec 1. PMID 33349443
• Weixler V, Lapusca R, Grangl G, Guariento A, Saeed MY, Cowan DB, Del Nido PJ, McCully JD, Friehs I. Autogenous mitochondria transplantation for treatment of right heart failure. J Thorac Cardiovasc Surg. 2021 Jul;162(1):e111-e121. doi: 10.1016/j.jtcvs.2020.08.011. Epub 2020 Aug 10. PMID 32919774
• Doulamis IP, Guariento A, Duignan T, Kido T, Orfany A, Saeed MY, Weixler VH, Blitzer D, Shin B, Snay ER, Inkster JA, Packard AB, Zurakowski D, Rousselle T, Bajwa A, Parikh SM, Stillman IE, Del Nido PJ, McCully JD. Mitochondrial transplantation by intra-arterial injection for acute kidney injury. Am J Physiol Renal Physiol. 2020 Sep 1;319(3):F403-F413. doi: 10.1152/ajprenal.00255.2020. Epub 2020 Ju PMID 32686525
• Orfany A, Arriola CG, Doulamis IP, Guariento A, Ramirez-Barbieri G, Moskowitzova K, Shin B, Blitzer D, Rogers C, Del Nido PJ, McCully JD. Mitochondrial transplantation ameliorates acute limb ischemia. J Vasc Surg. 2020 Mar;71(3):1014-1026. doi: 10.1016/j.jvs.2019.03.079. Epub 2019 Jul 26. PMID 31353269
• Ramirez-Barbieri G, Moskowitzova K, Shin B, Blitzer D, Orfany A, Guariento A, Iken K, Friehs I, Zurakowski D, Del Nido PJ, McCully JD. Alloreactivity and allorecognition of syngeneic and allogeneic mitochondria. Mitochondrion. 2019 May;46:103-115. doi: 10.1016/j.mito.2018.03.002. Epub 2018 Mar 26. PMID 29588218
• McCully JD, Levitsky S, Del Nido PJ, Cowan DB. Mitochondrial transplantation for therapeutic use. Clin Transl Med. 2016 Mar;5(1):16. doi: 10.1186/s40169-016-0095-4. Epub 2016 Apr 29. PMID 27130633
• Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016 Jul 28;535(7613):551-5. doi: 10.1038/nature18928. PMID 27466127

Identifiers

NCT: NCT04998357 · STUDY00006638

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗