The Guardian: Simplifying development of next-generation rare disease therapies

Rare diseases are individually rare but collectively common. About 80% of rare diseases are genetic and hard to treat.

Rare diseases are hard to treat due to the human genome’s complexity. This complexity results in the development of diverse, disease-causing mutations. Consequently, traditional approaches to drug development have become expensive and ineffective.

Exploiting new genomics advances

Genomics advances mean patients can be screened to determine whether they carry disease-causing variants in their genome. In parallel, the biotechnology industry has developed new treatments using antibodies, such as antibody-drug conjugates (ADCs), that can target specific diseased cells.

This has led to new classes of precision cancer treatments, some of which are now first-line treatments in metastatic breast cancer. It’s time to start exploiting these precision approaches to address rare diseases.

Creating targeted therapies for DM1

Myotonic Dystrophy Type 1 (DM1) is a type of muscular dystrophy that brings about progressive muscle loss and weakness and is caused by a mutation in the DMPK gene. Affecting 1 in 2,100, it is diagnosed through genetic testing, including at the prenatal stage. It has no cure and is managed through mobility aids and pain relief.

Today, researchers are developing new drugs that address the genetic basis of DM1, intending to halt and, hopefully, reverse progression. These therapies are based on short strands of DNA or RNA called oligonucleotides. They interact directly with the faulty machinery within a cell to enable it to operate correctly. The challenge is how to deliver these oligonucleotides into the affected cells in the body.

Power of antibody-oligonucleotide conjugates

Researchers have found ways to tap into existing proven targeting technologies used in other successful antibody therapies. By tethering the targeting antibody to the active oligonucleotide, thus creating ‘antibody-oligonucleotide conjugates‘ (AOCs). For DM1, these AOCs search out the diseased muscle cells, enter the cell nucleus (its brain) and neutralize the effect of the mutant DMPK gene.

Clinical trials have demonstrated that AOCs induce the required gene regulation, are safe and produce functional improvements in DM1 patients. Using an AOC approach, off-the-shelf components can be assembled to create complex precision medicines, offering potentially more cost-effective treatments for rare disease patients.

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