Gene Therapy for Krabbe Disease
(REKLAIM Trial)
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: Forge Biologics, Inc
No Placebo Group
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?This trial tests a single dose of a virus carrying a healthy gene in patients with severe forms of Krabbe disease. The virus helps by delivering the healthy gene to the patient's cells. Gene therapy has shown promise in extending survival in previous studies.
Do I have to stop taking my current medications for the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive drugs due to anti-AAV10 antibody titers, you may need to continue them as part of the study's immune response management.
What data supports the idea that Gene Therapy for Krabbe Disease is an effective treatment?
The available research shows that Gene Therapy for Krabbe Disease, specifically using AAVrh10-GALC, can significantly improve outcomes in animal models. In studies with twitcher mice, which are used to model Krabbe Disease, increasing the dose of the gene therapy without bone marrow transplantation led to longer lifespans and normal physical characteristics. Another study showed that a single injection of the therapy after bone marrow transplantation greatly extended the mice's lifespan and improved their behavior. Additionally, an engineered version of the therapy using AAV9 significantly improved motor function and extended the median lifespan of treated mice compared to untreated ones. These results suggest that Gene Therapy could be a more effective treatment option than the current standard, which is hematopoietic stem cell transplantation, as it may avoid some of the associated side effects and improve overall outcomes.
12345What safety data exists for gene therapy treatment for Krabbe Disease?
The safety data for gene therapy treatment for Krabbe Disease, specifically using AAVrh10-GALC, has been primarily evaluated in animal models such as twitcher mice and a canine model. Studies have shown that high doses of AAVrh10-GALC can significantly extend lifespan and improve neurological function in these models without the need for bone marrow transplantation (BMT). In twitcher mice, high doses of the viral vector resulted in normal weight, appearance, and behavior, with no signs of neuro-inflammation. In the canine model, intravenous AAVrh10 alone improved nerve conduction and normalized enzyme activity in the peripheral nervous system, although the best results were seen when combined with HSCT. No significant adverse effects, such as liver pathology or hepatic neoplasia, were reported in these studies, suggesting a favorable safety profile for the gene therapy.
12346Is the treatment FBX-101 a promising treatment for Krabbe Disease?
Yes, FBX-101 is a promising treatment for Krabbe Disease. Studies in mice show that it can significantly extend lifespan and improve behavior when combined with bone marrow transplantation. It may also work well on its own at higher doses, potentially eliminating the need for other treatments. This suggests it could greatly improve outcomes for patients with Krabbe Disease.
12345Eligibility Criteria
This trial is for children with Krabbe Disease who've had a stem cell transplant at least 90 days before. They must have certain diagnostic criteria met, including specific test results or mutations, and sufficient engraftment of donor cells. Children can't join if they have recent infections, MRI or lumbar puncture contraindications, used investigational products recently, live virus immunizations within the last month, severe organ function issues, neurocognitive deficits not due to Krabbe disease, heart problems without pulmonary hypertension evidence or previous gene therapy treatments.Inclusion Criteria
I am getting or have had a transplant for Krabbe disease diagnosed in infancy.
I had a transplant over 3 months ago and meet the chimerism requirements.
I am eligible for a stem cell transplant or had one at least 21 days ago.
+2 more
Exclusion Criteria
Any other medical condition, serious intercurrent illness, other genetic condition or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study
I have not received any live virus vaccines in the last 30 days.
Immunoassay with total anti-AAVrh10 antibody titers of >1:100
+9 more
Participant Groups
The study tests FBX-101 in kids who previously received a stem cell transplant for Krabbe Disease. It's an escalating dose trial where participants get one infusion of this gene therapy product. The effects will be compared to data from untreated and transplanted patients with infantile and late infantile forms of the disease.
2Treatment groups
Experimental Treatment
Group I: Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC)Experimental Treatment1 Intervention
N=3-6 patients with Infantile or Late Infantile Krabbe disease will receive a single infusion at the high dose
Group II: Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC)Experimental Treatment1 Intervention
N=3 patients with Infantile or Late Infantile Krabbe disease will receive a single infusion at the low dose
FBX-101 is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as FBX-101 for:
- Krabbe disease
🇺🇸 Approved in United States as FBX-101 for:
- Krabbe disease
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Duke University Medical CenterDurham, NC
Children's Hospital of Orange County (CHOC)Orange, CA
University of Michigan Hospitals - Michigan MedicineAnn Arbor, MI
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Who Is Running the Clinical Trial?
Forge Biologics, IncLead Sponsor
References
Can early treatment of twitcher mice with high dose AAVrh10-GALC eliminate the need for BMT? [2021]Introduction: Krabbe disease (KD) is an autosomal recessive disorder caused by mutations in the galactocerebrosidase (GALC) gene resulting in neuro-inflammation and defective myelination in the central and peripheral nervous systems. Most infantile patients present with clinical features before six months of age and die before two years of age. The only treatment available for pre-symptomatic or mildly affected individuals is hematopoietic stem cell transplantation (HSCT). In the animal models, combining bone marrow transplantation (BMT) with gene therapy has shown the best results in disease outcome. In this study, we examine the outcome of gene therapy alone. Methods: Twitcher (twi) mice used in the study, have a W339X mutation in the GALC gene. Genotype identification of the mice was performed shortly after birth or post-natal day 1 (PND1), using polymerase chain reaction on the toe clips followed by restriction enzyme digestion and electrophoresis. Eight or nine-day-old affected mice were used for gene therapy treatment alone or combined with BMT. While iv injection of 4 × 1013 gc/kg of body weight of viral vector was used originally, different viral titers were also used without BMT to evaluate their outcomes. Results: When the standard viral dose was increased four- and ten-fold (4X and 10X) without BMT, the lifespans were increased significantly. Without BMT the affected mice were fertile, had the same weight and appearance as wild type mice and had normal strength and gait. The brains showed no staining for CD68, a marker for activated microglia/macrophages, and less astrogliosis than untreated twi mice. Conclusion: Our results demonstrate that, it may be possible to treat human KD patients with high dose AAVrh10 without blood stem cell transplantation which would eliminate the side effects of HSCT.
Long-term Improvements in Lifespan and Pathology in CNS and PNS After BMT Plus One Intravenous Injection of AAVrh10-GALC in Twitcher Mice. [2018]Krabbe disease is an autosomal recessive disorder resulting from defects in the lysosomal enzyme galactocerebrosidase (GALC). GALC deficiency leads to severe neurological features. The only treatment for presymptomatic infantile patients and later-onset patients is hematopoietic stem cell transplantation (HSCT). This treatment is less than ideal with most patients eventually developing problems with gait and expressive language. Several naturally occurring animal models are available, including twitcher (twi) mice, which have been used for many treatment trials. Previous studies demonstrated that multiple injections of AAVrh10-GALC into the central nervous system (CNS) of neonatal twi mice resulted in significant improvements. Recently we showed that one i.v. injection of AAVrh10-GALC on PND10 resulted in normal GALC activity in the CNS and high activity in the peripheral nervous system (PNS). In the present study, a single i.v. injection of AAVrh10-GALC was given 1 day after bone marrow transplantation (BMT) on PND10. The mice show greatly extended lifespan and normal behavior with improved CNS and PNS findings. Since HSCT is the standard of care in human patients, adding this single i.v. injection of viral vector may greatly improve the treatment outcome.
An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice. [2023]Krabbe disease is an inherited neurodegenerative disease caused by mutations in the galactosylceramidase gene. In the infantile form, patients die before 3 years of age. Systemic adeno-associated virus serotype 9 (AAV9) gene therapy was recently shown to reverse the disease course in human patients in another lethal infantile neurodegenerative disease. To explore AAV9 therapy for Krabbe disease, we engineered a codon-optimized AAV9 galactosylceramidase vector. We further incorporated features to allow AAV9-derived galactosylceramidase to more efficiently cross the blood-brain barrier and be secreted from transduced cells. We tested the optimized vector by a single systemic injection in the twitcher mouse, an authentic Krabbe disease model. Untreated twitcher mice showed characteristic neuropathology and motion defects. They died prematurely with a median life span of 41 days. Intravenous injection in 2-day-old twitcher mice reduced central and peripheral neuropathology and significantly improved the gait pattern and body weight. Noticeably, the median life span was extended to 150 days. Intraperitoneal injection in 6- to 12-day-old twitcher mice also significantly improved the motor function, body weight, and median life span (to 104 days). Our results far exceed the ≤70 days median life span seen in all reported stand-alone systemic AAV therapies. Our study highlights the importance of vector engineering for Krabbe disease gene therapy. The engineered vector warrants further development.
Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. [2020]Introduction: Krabbe disease (KD) is an autosomal recessive lysosomal disorder caused by mutations in the galactocerebrosidase (GALC) gene. This results in defective myelination in the peripheral and central nervous systems due to low GALC activity. Treatment at this time is limited to hematopoietic stem cell transplantation (HSCT) in pre-symptomatic individuals. While this treatment extends the lives of treated individuals, most have difficulty walking by the end of the first decade due to peripheral neuropathy. Studies in the murine model of KD, twitcher (twi) combining bone marrow transplantation (BMT) with AAVrh10-mGALC showed a great extension of life from 40 days to about 400 days, with some living a full life time. Methods: In order to find the optimum conditions for dosing and timing of this combined treatment, twi mice were injected with five doses of AAVrh10-mGALC at different times after BMT. Survival, as well as GALC expression were monitored along with studies of sciatic nerve myelination and possible liver pathology. Results: Dosing had a pronounced effect on survival and measured GALC activity. There was window of time after BMT to inject the viral vector and see similar results, however delaying both the BMT and the viral injection shortened the lifespans of the treated mice. Lowering the viral dose too much decreased the correction of the sciatic nerve myelination. There was no evidence for hepatic neoplasia. Conclusion: These studies provide the conditions optimum for successfully treating the murine model of KD. There is some flexibility in dosing and timing to obtain a satisfactory outcome. These studies are critical to the planning of a human trial combining the "standard of care", HSCT, with a single iv injection of AAVrh10-GALC.
rAAV2-Mediated Restoration of GALC in Neural Stem Cells from Krabbe Patient-Derived iPSCs. [2023]Krabbe disease is a rare neurodegenerative fatal disease. It is caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC), which results in progressive accumulation of galactolipid substrates in myelin-forming cells. However, there is still a lack of appropriate neural models and effective approaches for Krabbe disease. We generated induced pluripotent stem cells (iPSCs) from a Krabbe patient previously. Here, Krabbe patient-derived neural stem cells (K-NSCs) were induced from these iPSCs. By using nine kinds of recombinant adeno-associated virus (rAAV) vectors to infect K-NSCs, we found that the rAAV2 vector has high transduction efficiency for K-NSCs. Most importantly, rAAV2-GALC rescued GALC enzymatic activity in K-NSCs. Our findings not only establish a novel patient NSC model for Krabbe disease, but also firstly indicate the potential of rAAV2-mediated gene therapy for this devastating disease.
Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy. [2023]Hematopoietic stem cell transplantation (HSCT) is the only approved treatment for presymptomatic infantile globoid cell leukodystrophy (GLD [Krabbe disease]). However, correction of disease is not complete, and outcomes remain poor. Herein we evaluated HSCT, intravenous (IV) adeno-associated virus rh10 vector (AAVrh10) gene therapy, and combination HSCT + IV AAVrh10 in the canine model of GLD. While HSCT alone resulted in no increase in survival as compared with untreated GLD dogs (∼16 weeks of age), combination HSCT + IV AAVrh10 at a dose of 4E13 genome copies (gc)/kg resulted in delayed disease progression and increased survival beyond 1 year of age. A 5-fold increase in AAVrh10 dose to 2E14 gc/kg, in combination with HSCT, normalized neurological dysfunction up to 2 years of age. IV AAVrh10 alone resulted in an average survival to 41.2 weeks of age. In the peripheral nervous system, IV AAVrh10 alone or in addition to HSCT normalized nerve conduction velocity, improved ultrastructure, and normalized GALC enzyme activity and psychosine concentration. In the central nervous system, only combination therapy at the highest dose was able to restore galactosylceramidase activity and psychosine concentrations to within the normal range. These data have now guided clinical translation of systemic AAV gene therapy as an addition to HSCT (NCT04693598, NCT05739643).