RESKUE: Gene Transfer Clinical Trial for Krabbe Disease
Study Details
Study Description
Brief Summary
This is a nonblinded, non-randomized dose escalation study of intravenous AAVrh10 after hematopoietic stem cell transplantation (HSCT) in which subjects will receive standard of care hematopoietic cell transplantation for Krabbe disease, followed by a single infusion of an adeno-associated virus gene therapy product. Extensive natural history subjects will be used to compare as control group.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC) Participants will receive a single infusion at the lower dose (N=3 participants) |
Biological: FBX-101
A replication-deficient adeno-associated virus gene transfer vector expressing the human galactocerebrosidase (GALC) cDNA will be delivered one-time through a venous catheter inserted into a peripheral limb vein.
Other Names:
|
| Experimental: Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC) Participants will receive a single infusion at the higher dose (N=3 participants) |
Biological: FBX-101
A replication-deficient adeno-associated virus gene transfer vector expressing the human galactocerebrosidase (GALC) cDNA will be delivered one-time through a venous catheter inserted into a peripheral limb vein.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Safety as assessed by incidence and severity of adverse events and serious adverse events that are attributed to FBX-101. [24 months]
- Safety as assessed by HSCT incident of engraftment. [24 months]
Secondary Outcome Measures
- Efficacy as assessed by improvement of probability to achieve independent sitting compared to untreated patients or those receiving HSCT only. [12 months and 24 months]
- Efficacy as assessed by improvement of gross motor function as measured by Peabody Developmental Motor Scale 2nd Edition (PDMS-2) above a functional age equivalent of 12 months compared to untreated patients or those receiving HSCT only [12 months and 24 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
- Diagnosis of infantile Krabbe disease, characterized by the following criteria outlined below:
- Galactocerebrosidase (GALC) activity levels in leukocytes compatible with the diagnosis of Krabbe disease according to the lab releasing the results; AND AT
LEAST ONE OF THE FOLLOWING:
-
Elevated psychosine predictive of infantile disease ≥ 9.0 nmol/L; OR
-
Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR
-
Two predicted pathogenic GALC mutations.
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Age at the time of screening: 1 day to 12 months
-
Participant has been deemed eligible for treatment with HSCT (standard of care) or is within two weeks of HSC infusion
-
Participant's parents or legal guardian consents to participate in the study and provides informed consent according to IRB guidelines prior to any study procedures being performed
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Parent(s) and/or legal guardian able to comply with the clinical protocol
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Participant must have adequate organ function at time of screening as measured by:
-
Creatinine ≤ 1.5x upper limit of age appropriate normal and creatinine clearance ≥ 60 mL/min/1.73 m2
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Hepatic transaminases (ALT/AST) ≤ 2x age related upper limit of normal
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Ejection fraction of > 50% by echocardiogram or other appropriate study without evidence of pulmonary hypertension.
-
Pulmonary evaluation testing demonstrating resting pulse oximeter > 92% on room air
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Coagulation tests within 110% of normal ranges for age. (PT/INR and PTT)
Exclusion Criteria:
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History of prior treatment with a gene therapy product
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Presence of major congenital anomaly affecting the neurological system
-
Presence of any neurocognitive deficit or brain damage not attributable to Krabbe disease
-
Active aspiration
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Signs of active infection or disease from cytomegalovirus, adenovirus or other viruses
-
HIV positive
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Uncontrolled and progressive bacterial or fungal infection.
-
Presence of any contraindication for MRI
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Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions
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Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study
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Ongoing veno-occlusive disease (VOD) as determined by liver ultrasound (moderate ascites and static or retrograde portal vein flow) the day before FBX-101 infusion.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Michigan Hospitals - Michigan Medicine | Ann Arbor | Michigan | United States | 48109 |
Sponsors and Collaborators
- Forge Biologics, Inc
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Bascou, N., DeRenzo, A., Poe, M. & Escolar, M., 2018. A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life. Orphanet Journal of Rare Diseases, pp. 1-17.
- Beltran-Quintero, M. et al., 2019. Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months. Orphanet Journal of Rare Diseases, pp. 1-13.
- Bradbury, A. et al., 2018. AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease). Human Gene Therapy, pp. 785-801.
- Escolar, M. et al., 2005. Transplantation of Umbilical-Cord Blood in Babies with Infantile Krabbe's Disease. The New England Journal of Medicine, pp. 2069-2081.
- Escolar, M. et al., 2016. Clinical management of Krabbe disease. Journal of Neuroscience Research, pp. 1118-1125.
- Rafi, M., Luzi, P. & Wenger, D., 2020. Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. BioImpacts, pp. 105-115.
- Yoon, I., et al., 2021. Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease. Blood, pp. 1719-1730
Publications
None provided.- FBX-101-RESKUE