Abstract
Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood–brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141–150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases.
Highlights
Spinal muscular atrophy (SMA) is an inherited motor neuron disease and a leading genetic cause of infant mortality
We chemically synthesized a range of peptides (Table 1) that are analogues of endogenous peptides/proteins designed to bind to receptors at the blood–brain barrier (BBB) such as acetylcholine receptor (Ach-R), low-density lipoprotein receptor (LDLR), lipoprotein receptor-related protein 1 (LRP-1), apolipoprotein receptor (ApoER), transferrin receptor (TfR), or neuronal ganglioside receptor (GT1b-R)
splice-switching oligonucleotides (SSOs) are being developed for the treatment of various central nervous system (CNS) diseases such as frontotemporal dementia (FTD) [54], Menkes disease [55], Huntington’s disease [56], amyotrophic lateral sclerosis [57], and SMA [58,59,60,61,62]
Summary
Spinal muscular atrophy (SMA) is an inherited motor neuron disease and a leading genetic cause of infant mortality It is characterized by the loss of lower motor neurons, which results in progressive atrophy of voluntary muscle groups leading to paralysis and eventually premature death [1]. It is caused by the deletion of the survival motor neuron 1 (SMN1) gene in more than 95% of SMA patients [2]. The 10% of SMN2 transcripts that contain exon 7 and which produce full-length functional SMN protein cannot adequately compensate for the loss of SMN1 unless high copy numbers of SMN2 are present, in which case the severity of the disease is reduced [6,7]. The focus of most current therapeutic strategies is to increase the expression of SMN protein by induction of exon 7 inclusion in SMN2
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