Abstract
Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type – specific expression pattern of the disease – causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.
Highlights
Reviewed by: Allison Bradbury, Nationwide Children’s Hospital, United States Niek Peter Van Til, Amsterdam University Medical Center, Netherlands
Two further albeit later onset and usually milder leukodystrophies may benefit from astroglial gene transfer include chloride voltage gated channel 2 (CLCN2) related vacuolating leukoencephalopathy and the Oculodentodigital dysplasia with cerebral white matter abnormalities (ODDD), a hypomyelinating leukodystrophy caused by an autosomal dominant mutation in the Gap junction α 1 (Connexin-43) encoding GJA1 gene (Abrams and Scherer, 2012)
With regards to associated virus (AAV) – mediated in vivo gene therapy programs, which are establishing excellent safety and efficiency profiles, the recent tragic deaths of three patients in the high dose cohort of the ASPIRO trial targeting myotubular myopathy as well as preclinical evidence of toxicity and severe immune response associated with high vector doses following systemic AAV delivery are a reminder of the risks and imperative for refinement, around vector dose
Summary
We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future. Advances in diagnosis through magnetic resonance imaging (MRI), whole exon and whole genome sequencing have resolved broader non-myelin components of this white matter pathophysiology. In recognition of this the term leukoencephalopathy has partially supplanted leukodystrophy, but traditionally includes acquired disorders that do not have a hereditary cause. Substrate reduction and pharmacological treatments generally target symptoms and have been covered in excellent reviews, but drugs that effectively treat the underlying disease and improve progression remain elusive (Adang et al, 2017; van der Knaap et al, 2019).
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