Rafi MA, et al. Long-term Improvements in Lifespan and Pathology in CNS and PNS After BMT Plus One Intravenous Injection of AAVrh10 GALC in Twitcher Mice. Molecular Therapy. Volume 23, Issue 11, November 2015, Pages 1681-1690.
Hematopoietic stem cell transplant (HSCT) is the standard of care for patients with presymptomatic infantile-onset Krabbe disease and mildly affected late-onset patients. While this treatment is successful in correcting the central nervous system (CNS) and cognitive function of patients; unfortunately, the peripheral nervous system (PNS) does not respond the same and patients often experience decreased expressive language and the inability to walk on their own within a few years of this treatment.
In this very encouraging study, in addition to the HSCT, twitcher mice were also given a single intravenous (I.V.) injection of gene therapy using AAVrh10-GALC one day after the transplant. The mice showed greatly extended lifespans and normal behaviour with improved CNS and PNS findings.
- The median lifespan of untreated twitcher mice is ~40 days.
- Remarkable extended lifespan was shown when BMT and gene therapy using the AAV10 vector were combined.
- Of the 16 affected mice in this study, 10 were still living with the oldest mouse being over 340 days old and six others living >150 days.
- Four mice died and 3 of them were behaving normally till the end and did not show signs similar to the untreated mice.
- Mice treated with the combined therapy showed normal behaviour for almost their entire lives.
- The PNS was evaluated for disease. Normal myelination in the sciatic nerve continued throughout the lives of the mice treated with combination therapy.
- It is important to note that this study was conducted in twitcher mice and not humans.
- This study confirms the ability of the IV-injected AAVrh10 vector can deliver a corrective gene to the PNS and is especially important considering that most human patients treated by HSCT alone have significant issues with the PNS years after transplant.
- The addition of one dose of gene therapy after HSCT is able to provide high levels of GALC activity to many tissues including the PNS. Further studies are planned related to the timing of gene therapy after HSCT and the best dose for maximum survival is being explored.
- It is the hope that this combination therapy can lead to a clinical trial in human patients with Krabbe disease in the near future.