Potential treatment for SPG2 type HSP

Posted - December 2018 in Research Highlights

Good result from mice study

 

A single injection into the brains of newborn mice with spastic paraplegia 2 (SPG2) corrected the protein expression abnormalities caused by the mutation in the PLP1 gene. The effects lasted for three months, long enough for normal PLP production and normal myelination of nerves to take place. The compound, known as a morpholino oligomer, also produced a sustained reduction of inflammatory markers in the brains of the mice.

 

The results suggest that there is therapeutic potential in this treatment for Pelizaeus-Merzbacher disease (PMD), spastic paraplegia 2 (SPG2) and hypomyelination of early myelinating structures (HEMS).

 

Abstract

DNA variants of the proteolipid protein 1 gene (PLP1) that shift PLP1/DM20 alternative splicing away from the PLP1 form toward DM20 cause the allelic X-linked Pelizaeus-Merzbacher disease (PMD), spastic paraplegia 2 (SPG2) and hypomyelination of early myelinating structures (HEMS).

 

We designed a morpholino oligomer (MO-PLP) to block use of the DM20 5′ splice donor site, thereby shifting alternative splicing toward the PLP1 5′ splice site. Treatment of an immature oligodendrocyte cell line with MO-PLP significantly shifted alternative splicing toward PLP1 expression from the endogenous gene and from transfected human mini-gene splicing constructs harboring patient variants known to reduce the amount of the PLP1 spliced product. Additionally, a single intracerebroventricular injection of MO-PLP into the brains of neonatal mice, carrying a deletion of an intronic splicing enhancer identified in a PMD patient that reduces the PLP1 spliced form, corrected alternative splicing at both RNA and protein levels in the CNS.

 

The effect lasted to post-natal day 90, well beyond the early post-natal spike in myelination and PLP production. Further, the single injection produced a sustained reduction of inflammatory markers in the brains of the mice. Our results suggest that morpholino oligomers have therapeutic potential for the treatment of PMD, SPG2, and HEMS.

 

SOURCE: Mol Ther Nucleic Acids. 2018 Sep 7;12:420-432. doi: 10.1016/j.omtn.2018.05.019. Epub 2018 Jul 5. PMID: 30195779

 

Morpholino Antisense Oligomers as a Potential Therapeutic Option for the Correction of Alternative Splicing in PMD, SPG2 and HEMS.

 

Tantzer S1, Sperle K1, Kenaley K2, Taube J1, Hobson GM3.

 

1 Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.

2 Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; Department of Pediatrics/Neonatology, Christiana Care Health System, Newark, DE 19713, USA.

3 Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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