Antisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy (DMD) patients by... Show moreAntisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy (DMD) patients by interfering with the splicing process so mutated dystrophin transcripts become readable allowing production of partially functional dystrophin proteins, rather than nonfunctional dystrophins. After over 2 decades of research, 4 ASOs are FDA approved for DMD, but clinical effects are suboptimal due to limited delivery to skeletal muscle. At the same time, ASOs for brain diseases result in much more functional impact, because local delivery allows higher exposure to the target tissue at a low dose and infrequent treatment regimen. This has opened the way to develop ASOs in an individualized setting, as was exemplified by the development of Milasen to treat a patient with CLN7 Batten disease. In this perspective paper I will share my personal journey as one of the pioneers of ASO-mediated exon skipping development for DMD, currently applying expertise gained and lessons learned along the way to develop exon skipping ASOs for eligible patients with genetic brain diseases in a national and international setting. Show less
Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in... Show moreUrofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2, coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T>A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C>G variant encoding the missense p.Pro140Arg in trans with c.1099-1G>A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology. Show less
Aartsma-Rus, A.; Dooms, M.; Cam, Y. le; Od Expert Grp; Copenhagen Economics 2021
Today policy makers face the challenge to devise a policy framework that improves orphan medicinal product (OMP) development by creating incentives to deliver treatments where there are none and to... Show moreToday policy makers face the challenge to devise a policy framework that improves orphan medicinal product (OMP) development by creating incentives to deliver treatments where there are none and to authorize innovative and transformative treatments where treatments already exist. The European Expert Group on Orphan Drug Incentives (hereafter, OD Expert Group) came together in 2020 to develop policy proposals to facilitate EU policy makers to meet this challenge. The group brings together representatives of the broad rare disease community, including researchers, academia, patient representatives, members of the investor community, rare disease companies and trade associations. The group's work builds on the recognition that only an ambitious policy agenda developed in a multi-stakeholder setting can bring about the quantum leap needed to address unmet needs of rare disease patients today. Along the OMP development path, the OD Expert Group has identified four main needs that a policy revision should address: 1) Need to improve the R&D ecosystem for basic research and company take-up of development. 2) Need to improve the system of financial incentives and rewards. 3) Need to improve the flexibility, predictability and speed of the regulatory pathway. 4) Need to improve the coherence and predictability of demand and pricing for OMPs. This article presents the results of the OD Expert Group work as a set of guiding principles that the revision of the policy framework should follow and a set of 14 policy proposals that address the main needs of OMP development in Europe today. Show less
The drug development process is a long and arduous one, especially for rare diseases. Patient and patient representatives can and should be involved in this process from an early stage, since they... Show moreThe drug development process is a long and arduous one, especially for rare diseases. Patient and patient representatives can and should be involved in this process from an early stage, since they have the perspective of living with a disease on a daily basis and can best identify which symptoms are the largest burden and which benefits would be more important to them. In this perspective, we outline how patients can be involved optimally in drug development. We outline success factors such as finding the right partners, bilateral education, having realistic expectations, and an open and honest dialog with all stakeholders. Show less
