Karumuthil-Melethil S, Marshall MS, Heindel C, Jakubauskas B, Bongarzone E, Gray SJ. Intrathecal Administration of AAV/GALC Vectors in 10-11 Day old Twitcher Mic Improves Survival and is Enhanced by Bone Marrow TransplantA medical procedure whereby diseased bone marrow is replaced with healthy bone marrow. Often times, the patients’ bone marrow will be destroyed by high doses of certain chemotherapies and/or radiati. Journal of neuroscience research. 2016;94(11):1138-1151. doi:10.1002/jnr.23882. Click here to view publication
Background
Hematopoietic stem cell transplantTypically this refers to a bone marrow transplant with the goal of replacing non-working cells with healthy working cells. Bone marrow is a rich source of stem cells that have the unique ability to (HSCTHematopoietic stem cell transplantation (HSCT), a type of transplantation using multipotent hematopoietic stem cells typically derived from bone marrow, peripheral blood, or that from umbilical cord b) is the standard of care for patients with presymptomatic infantile-onset Krabbe disease and mildly affected late-onset patients; however, HSCT provides modest benefit in presymptomatic patients and falls well short of a cure. Recent studies have provided compelling evidence that a combination approach with gene therapyA type of therapy that offers hope and promise for a cure for many genetic disorders. A working copy of the gene replaces the non-working copy of the gene. Gene therapy is at the forefront of many plus HSCT is capable of treating different aspects of GLD and produce a significantly better therapeutic outcome than any single treatment. Gene transfer utilizing viral vectors to deliver the correct copy of the defective gene is becoming an attractive approach for treating several lysosomal storage diseases including Krabbe disease. Animal models, especially the twitcher mice, have helped researchers to better understand the pathology of the disease, as well as to test different therapeutic interventions.
Summary
This study, comparing three AAV vectors effectively demonstrates that gene therapy directly into the spinal fluid (lumbar intrathecal (IT) delivery) can significantly enhance the life-span of twitcher mice treated 10-11 days after birth and in combination with bone marrow transplant (BMT) further improves survival.
Results
- The present study compares three single-stranded (ss) AAV serotypes.
- The rAAV gene transfer facilitated GALC† gene biodistribution and detectable enzymatic activity throughout the CNS, as well as in sciatic nerve and liver.
- Analysis of brain, spinal cord, and sciatic nerve tissue showed significant improvement in preservation of myelinMyelin is an essential material your body uses to surround and protect nerve fibers., with ssAAV9 providing the greatest benefit.
- The median life span for the control mice was 40 days.
- The combined AAV+BMT treatments had further extensions in median lifespan to 79 and 57, for AAV9 and AAVrh10 respectively.
- It isn’t clear if the addition of BMT to the AAVrh10 treatment conferred a greater benefit, but the addition of BMT to the AAV9 treatment provided the best survival outcomes of all the treatments tested.
Key Points
- Two major conclusions from this study were observed: 1.) Using the intrathecal route of administration, AAV9 is the best of the 3 vectors tested. 2) BMT clearly synergized with the intrathecal AAV9 treatment, providing a substantial benefit over AAV9 alone.
- Taken together, studies identified that both AAV9 and AAVrh10 could provide a benefit, but only AAVrh10 was tested in Rafi et al. One can not infer from these results whether AAV9 might be better by an intravenous route of administration, and this remains to be tested.
- It is important to note that this study was conducted in twitcher mice and not humans.
- It is the hope that this combination therapy can lead to a clinical trialA clinical trial is research designed to understand the safety and efficacy of a drug, biologic or device. There are 4 phases to most clinical trials from Phase 1 that seeks to answer safety concern in human patients with Krabbe disease in the near future.