Krabbe disease (globoid cell leukodystrophy) is a rare inherited disorder caused by a deficiency in the
lysosomal enzyme galactosylceramidase (GALC) leading to destruction of the protective coating (myelin) of
nerve cells in the brain and throughout the nervous system. This fatal neurodegenerative disease affects
about 1 in 100,000 people in the US. In most cases, Krabbe symptoms develop in infants before 6 months of
age, often leading to death by age 2. Bone marrow transplantation is currently the only approved treatment
option for Krabbe patients, but only slows disease progression, and only when initiated in pre-symptomatic
children. More recent preclinical research has focused on gene transfer utilizing adeno-associated virus (AAV)
for long term expression of the normal GALC enzyme in the “twitcher” mouse model of Krabbe disease.
Although promising, this approach still shows deficiencies in distributing effective therapeutic doses to critical
parts of the brain and nervous system. BioStrategies LC has developed a lectin-based therapeutic delivery
module (RTB) that enables fused lysosomal enzymes to effectively target the CNS and treat neurological
symptoms following weekly ERT infusions, as demonstrated in several lysosomal disease animal models.
In this SBIR project, we propose to merge the benefits of AAV-mediated gene transfer technologies that
provide continuous long-term in vivo enzyme production with those of the RTB delivery technology to ensure
effective treatment of Krabbe’s progressive neurodegeneration. Gene expression cassettes fusing GALC with
BioStrategies’ RTB lectin will be packaged into recombinant adeno-associated virus for production and
subsequent administration to twitcher mice. Impacts on neurological disease progression and lifespan of mice
receiving AAV-vectored GALC-RTB fusions will be compared with untreated mice and those administered
AAV-vectored GALC alone. Specific aims of this Phase I feasibility study are 1) to construct GALC-RTB AAV
vectors and demonstrate their ability to produce fully functional GALC-RTB fusion product in mammalian cells
and mice; and 2) to compare therapeutic efficacy of AAV-mediated gene transfer of GALC-RTB versus GALC
in the Krabbe mouse model as measured by lifespan and imaging of brain and peripheral nerve pathologies.
Phase I milestones will show that our lectin fusion, GALC-RTB, can be expressed in the Krabbe twitcher
model via AAV gene transfer and demonstrate targeting of expressed GALC-RTB to hard-to-treat cells of CNS
and PNS tissue in twitcher (GALC-/-) mice, enhancing enzyme biodistribution and lifespan. Based on these
proof-of concept results, Phase II studies will assess the effects of dosage levels, timing, and routes of drug
administration on efficacy and safety of long-term treatment aimed at further moving this product to an IND.
The long-term goal of this project is to develop and bring this novel “delivery-enhanced” AAV gene therapy to
Krabbe patients. The feasibility established here will also support expanding the “RTB lectin-fused” gene
therapy treatment to other rare diseases having significant CNS and PNS tissue impairment.
