Gene Transfer Clinical Trial for Krabbe Disease

A Phase 1/2 Clinical Study of Intravenous Gene Transfer With an AAVrh10 Vector Expressing GALC in Krabbe Subjects Receiving Hematopoietic Stem Cell Transplantation (RESKUE)

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.

Inclusion Criteria:

1. 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; AND AT LEAST ONE OF THE FOLLOWING:
   • Elevated psychosine levels predictive of infantile disease onset by DBS; OR
   • Imaging or neurophysiological findings consistent with Krabbe disease (CSF, MRI, NCV, ABR); OR
   • Two GALC mutations predictive to result in infantile onset phenotype.

2. Age at the time of screening: 1 day to 12 months

3. Participant has been deemed eligible for treatment with HSCT (standard of care) and a fully myeloablative reduced intensity/toxicity conditioning regimen (RIC/RTC) is/has been used

4. 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

5. Parent(s) and/or legal guardian able to comply with the clinical protocol

6. 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
   • Hepatic transaminases (ALT/AST) ≤ 2x age related upper limit of normal
   • Ejection fraction of > 50% by echocardiogram or other appropriate study without evidence of pulmonary hypertension
   • Pulmonary evaluation testing demonstrating resting pulse oximeter > 95% on room air
   • Coagulation tests within 110% of normal ranges for age. (PT/INR and PTT)

Exclusion Criteria:

1. History of prior treatment with a gene therapy product
2. Presence of major congenital anomaly or any other condition that affects neurodevelopmental function
3. Presence of any neurocognitive deficit or brain damage not attributable to Krabbe disease
4. Active aspiration
5. Signs of active infection or disease from cytomegalovirus, adenovirus or other viruses
6. HIV positive
7. Uncontrolled and progressive bacterial or fungal infection
8. Presence of any contraindication for MRI
9. Use of any investigational product prior to study enrollment or current enrollment in another study that involves clinical interventions
10. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study
11. 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.