Rare disease therapeutics: The future of medical genetics in a changing landscape

Connolly, Christopher; Quinonez, Shane C.; Ames, Elizabeth G.

doi:10.1016/j.gim.2022.11.007

Cited by 3 publications

(3 citation statements)

References 16 publications

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“…Developing orphan drugs can improve a pharmaceutical company's reputation by showing that they are willing to invest in the development of treatments for rare and often neglected diseases. The market for orphan drugs is expected to continue to grow in the coming years, and many pharmaceutical companies view the development of orphan drugs as a way to diversify their product portfolio and ensure longterm sustainability [10][11][12] . Developing drugs for rare genetic disorders is a complex and challenging process, and not all companies are able to successfully develop and bring an orphan drug to market.…”

Section: Unmet Needsmentioning

confidence: 99%

“…Developing orphan drugs can improve a pharmaceutical company’s reputation by demonstrating its willingness to invest in treating rare and often neglected diseases. Several pharmaceutical companies consider the development of orphan drugs a way to diversify their product portfolios and ensure long-term sustainability [ 10 - 12 ]. The development of drugs for rare genetic disorders is a complex and challenging process, and not all companies can do so successfully.…”

Section: Socioeconomic Burden Of Rare Genetic Disordersmentioning

confidence: 99%

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Development of orphan drugs for rare diseases

Yoo¹

2024

Clin Exp Pediatr

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Most rare diseases (orphan diseases) still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to expedite the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. There are several strategies for the development of orphan drugs for rare genetic disorders including protein replacement therapies, small molecule therapies(e.g. substrate reduction therapy, chemical chaperone therapy, cofactor therapy, expression modification therapy, read through therapy), monoclonal antibodies, antisense oligonucleotide, small interfering RNA or exon skipping therapies, gene replacement and direct genome editing therapies, mRNA therapy, and cell therapy as well as drug repurposing. Each strategy has its strength and limitations for orphan drug development. Furthermore, numerous hurdles are present in clinical trials in rare genetic disease because of difficulty in patient recruitment, unknown molecular physiology and natural history of the disease, ethical concerns about pediatric patients, and regulatory challenges. To address these barriers, the rare genetic diseases community including academic institutions, industry, patient advocacy groups, foundations, payers and government regulatory and research organizations, must be engaged as a partnership in discussions about the issues.

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Section: Unmet Needsmentioning

confidence: 99%

Section: Socioeconomic Burden Of Rare Genetic Disordersmentioning

confidence: 99%

Development of orphan drugs for rare diseases

Yoo¹

2024

Clin Exp Pediatr

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“…Since the first mRNA vaccine (BNT162b2) was approved by the FDA at the end of 2020, mRNA-based therapies have experienced rapid development [ 1 , 2 , 3 , 4 , 5 ]. Notably, mRNA drugs have the following benefits: tremendous potency against various diseases, including infectious diseases, cancers, and rare diseases; extremely low dosage for greater security; incredibly rapid drug discovery; and large-scale drug development [ 6 , 7 , 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Effective Synthesis of High-Integrity mRNA Using In Vitro Transcription

He,

Zhang,

Zou

et al. 2024

Molecules

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: mRNA vaccines are entering a period of rapid development. However, their synthesis is still plagued by challenges related to mRNA impurities and fragments (incomplete mRNA). Most impurities of mRNA products transcribed in vitro are mRNA fragments. Only full-length mRNA transcripts containing both a 5′-cap and a 3′-poly(A) structure are viable for in vivo expression. Therefore, RNA fragments are the primary product-related impurities that significantly hinder mRNA efficacy and must be effectively controlled; these species are believed to originate from either mRNA hydrolysis or premature transcriptional termination. In the manufacturing of commercial mRNA vaccines, T7 RNA polymerase-catalyzed in vitro transcription (IVT) synthesis is a well-established method for synthesizing long RNA transcripts. This study identified a pivotal domain on the T7 RNA polymerase that is associated with erroneous mRNA release. By leveraging the advantageous properties of a T7 RNA polymerase mutant and precisely optimized IVT process parameters, we successfully achieved an mRNA integrity exceeding 91%, thereby further unlocking the immense potential of mRNA therapeutics.

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Effective Synthesis of mRNA during In Vitro Transcription with Fewer Impurities Produced

He,

Geng,

et al. 2024

Molecules

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The remarkable efficacy of COVID-19 vaccines has established mRNA as a highly promising biomedical technology. However, the adequate application of mRNA therapeutics necessitates additional measures to mitigate the inherent immunogenicity, which is predominantly caused by dsRNA. As a byproduct of the in vitro transcription of mRNA, dsRNA was reported to be originated through several distinct mechanisms, including the extension of 3′ loop-back hairpins, the extension of hybridized abortive transcripts, and promoter-independent transcription. The intricate mechanisms involved pose a dilemma as the reduction in dsRNA results in a concomitant decrease in other critical quality attributes of mRNA. Here, we demonstrate that the promoter binding motifs of T7 RNA polymerase directly impact the production of promoter-independent transcription-based dsRNA. Specifically, the G753A mutation significantly reduces the formation of dsRNA byproducts, which can further combine with modified nucleotides to enhance the effectiveness of dsRNA mitigation and with previously reported high-integrity mutation K389A to minimize side effects. Accordingly, the present study reports a cost-effective approach to synthesize high-purity, less immunostimulatory mRNA by using an engineered T7 RNA polymerase mutant.

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Rare disease therapeutics: The future of medical genetics in a changing landscape

Cited by 3 publications

References 16 publications

Development of orphan drugs for rare diseases

Development of orphan drugs for rare diseases

Effective Synthesis of High-Integrity mRNA Using In Vitro Transcription

Effective Synthesis of mRNA during In Vitro Transcription with Fewer Impurities Produced

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