Gene and Cellular Therapies for Leukodystrophies

Abstract

Leukodystrophies are a heterogenous group of inherited, degenerative encephalopathies, that if left untreated, are often lethal at an early age. Although some of the leukodystrophies can be treated with allogeneic hematopoietic stem cell transplantation, not all patients have suitable donors, and new treatment strategies, such as gene therapy, are rapidly being developed. Recent developments in the field of gene therapy for severe combined immune deficiencies, Leber's amaurosis, epidermolysis bullosa, Duchenne's muscular dystrophy and spinal muscular atrophy, have paved the way for the treatment of leukodystrophies, revealing some of the pitfalls, but overall showing promising results. Gene therapy offers the possibility for overexpression of secretable enzymes that can be released and through uptake, allow cross-correction of affected cells. Here, we discuss some of the leukodystrophies that have demonstrated strong potential for gene therapy interventions, such as X-linked adrenoleukodystrophy (X-ALD), and metachromatic leukodystrophy (MLD), which have reached clinical application. We further discuss the advantages and disadvantages of ex vivo lentiviral hematopoietic stem cell gene therapy, an approach for targeting microglia-like cells or rendering cross-correction. In addition, we summarize ongoing developments in the field of in vivo administration of recombinant adeno-associated viral (rAAV) vectors, which can be used for direct targeting of affected cells, and other recently developed molecular technologies that may be applicable to treating leukodystrophies in the future.

Keywords: adeno-associated viral vectors; gene therapy; lentiviral vectors; leukodystrophies; stem cell transplantation.

Figure 2

Therapeutic options for the treatment of autosomal recessively inherited leukodystrophies. The choice of AAV capsid can vary depending on the specific type of cells, brain region, age, species and intended application. Several rAAV capsid types have been identified as efficient at transducing neurons [109]. Efficient transduction of microglia, using rAAV capsids can be challenging, as microglia have unique properties and limited susceptibility to traditional AAV vectors [124]. AAV6 derivatives have shown promise in this field [125,126]. Efficient transduction of oligodendrocytes, using rAAV capsids can be challenging. Oligodendrocytes have been traditionally less susceptible to AAV transduction compared to other CNS cell types like neurons, but there are AAV capsids with known oligodendrocyte tropism [113]. While a number of AAV capsids have shown a propensity for astrocyte transduction, the efficiency may vary [127]. In vivo delivery of rAAV vectors can be obtained through multiple routes of administration (RoA), including intraparenchymal injection (IP), intracerebroventricular (ICV), lumbar intrathecal (IT), intra cisterna magna (ICM) IV injections, and even through nasal delivery. The most commonly used rAAV vector types are provided in bold. Use of gammaretroviral (γRV) or lentiviral (LV) vectors for the transfer of lacking genes is performed ex vivo after enrichment of hematopoietic stem cells. Of note: PhP.B and PhP.eB vectors are BL/6 mouse strain specific, but have been shown to function in other species as well [102,103,128,129].

Figure 1

Timelines of ALD, MLD and GLD: from recognition to the development of gene therapy. Development of gene therapy for the major primary leukodystrophies has taken well over a century to reach clinics. However, it is expected that the development and approval of gene therapy for similar diseases may be much faster since most of the footwork has been carried out and many of the pitfalls have been revealed and tackled in subsequent studies. AR: autosomal recessive; GT: gene therapy.