Rare disease drug discovery: the technologies driving ‘orphan’ therapeutics forward
Rare diseases have long posed a challenge in the field of medicine. Limited treatment options and diagnostic hurdles mean patient prognosis is often not positive; however, some groundbreaking technologies are offering hope of treatment to the small number of people affected by these so-called ‘orphan’ diseases. This Rare Disease Day, we explore how innovations like AI and gene editing are changing the game in rare disease research by advancing drug discovery and development.
Rare diseases, as you might expect, are incredibly uncommon, affecting fewer than one in 2000 people. They are often associated with impaired quality of life and reduced lifespan – it is estimated that a third of patients die before the age of five – but there are shockingly few treatment options, despite an obvious need. Over 7000 rare diseases have been identified so far, however only around 5% of these have a licensed treatment.
Because of their low prevalence and therefore lack of profitability, this group of conditions has been largely neglected by scientific and pharmaceutical communities, and as a result is also referred to as ‘orphan’ diseases.
In 1983, the US Orphan Drug Act marked the first legislative effort to promote rare disease drug development, resulting in hundreds of new orphan drugs, although these were largely tailored toward delaying disease progression and reducing the impact on a patient’s life, as opposed to being curative.
Speaking exclusively to BioTechniques about the pitfalls of finding new treatments, Venkata Indurthi, Chief Scientific Officer at Aldevron (ND, USA), explained that “rare disease drug discovery faces several interconnected challenges. Technical complexity, high development costs, reimbursement limitations and small patient populations are major barriers. These issues affect both the clinical feasibility of trials and the technological approaches required to develop effective therapies, particularly for ultra‑rare conditions.”
In the decades since the Orphan Drug Act, novel technologies have emerged with the potential to bridge this vast gap in rare disease research, fast-tracking drug discovery and development for this group of debilitating conditions. Leading the charge, according to Indurthi, are RNA‑based therapies, gene editing and AI. “These platforms enable more precise target identification, offer new ways to correct genetic errors and help reduce development timelines that were previously prohibitive for rare disease programs.”
AI and machine learning
The advent of AI has transformed so many aspects of healthcare, and the treatment of rare diseases is no different. Data on orphan diseases is usually scarce, hence AI’s ability to integrate and analyze information from different sources makes it a valuable tool in this field.
“AI is advancing rare disease drug discovery by improving target identification, enabling predictive modeling and helping teams narrow down design of experiments,” Indurthi asserted. “[It] reduces both time and cost by focusing development efforts on the most promising approaches earlier in the process, which is especially important when patient populations and available data are limited.”
According to a 2024 review, at least 75 AI-discovered molecules have entered clinical trials since 2015. Of those that completed Phase I trials, 80–90% were successful – significantly more than historic industry averages.
Some of these compounds are already making a difference in rare disease research. For example, last year, researchers published findings from a Phase IIa clinical trial of a generative AI-discovered drug for idiopathic pulmonary fibrosis, a rare lung disease for which there is no known cure. The compound, developed by Insilico Medicine (MA, USA), inhibits a protein called Nck-interacting kinase, which was identified using AI as a potential drug target. The team also used AI to design the inhibitor, rentosertib, which fared well in the trial.
Despite the promise of AI to facilitate the discovery, design and development of new therapies, to date, no AI-discovered molecule has received final approval from the US Food and Drug Administration (FDA; MD, USA) for commercial use. However, AI is breaking new ground in repurposing existing drugs for the treatment of rare diseases.
Finding new uses for established therapeutics beyond their original indications greatly reduces development time and cost, which can help address the unmet clinical need in rare disease research.
In the last few years, AI has helped drive this forward, facilitating numerous potential repurposed treatments for orphan diseases. Last year, scientists reported that an AI tool combed through 4000 existing medications, identifying one that led to the remission of a patient with idiopathic multicentric Castleman’s disease, a rare autoimmune disorder. The drug, adalimumab, is a monoclonal antibody already FDA-approved to treat conditions including arthritis and Crohn’s disease.
Similarly, in 2023, digital drug discovery company Delta4 (Vienna, Austria) announced it had identified a potential, pre-existing therapeutic option for focal segmental glomerulosclerosis – a kidney condition with inadequate treatment options – using its Hyper-C AI software platform. In an animal model of the disease, the anti-platelet drug clopidogrel was shown to alleviate disease progression, demonstrating its promise for clinical trials.
In 2024, researchers published a new AI model, TxGNN, which uses a graph neural network and metric learning module to rank drugs as potential indications and contraindications. From nearly 8000 medicines, the model identified therapeutic candidates and predicted side effects for more than 17,000 diseases, even those with limited treatment options or no existing drugs. When benchmarked against leading AI models for drug repurposing, the new tool improved prediction accuracy for indications by almost 50%, on average, and around 35% for contraindications.
These examples represent just a handful of the AI tools currently being developed to aid rare disease drug discovery, which, hopefully, will continue to improve the outlook for patients with these overlooked conditions.
Rare disease drug development: challenges, support and hopes for the future
Exploring the challenges with rare disease drug development, how they can be addressed and what the future may hold for the rare disease landscape.
Gene editing
Meanwhile, the likes of CRISPR and other gene-editing technologies are making similar strides in this area of research.
Around 80% of rare diseases have a known genetic origin, and most are caused by a single-gene mutation, meaning that gene-editing systems, including knock‑in, base editing and prime editing, are well-positioned to provide therapeutic options to patients.
The world’s first personalized CRISPR therapy made headlines last year after it successfully treated a baby with the rare metabolic disease severe carbamoyl phosphate synthetase 1 (CPS1) deficiency. The breakthrough therapy was developed by Aldevron and Integrated DNA Technologies (IA, USA) and uses lipid nanoparticle-delivered base-editing to correct a faulty enzyme in the liver that converts ammonia to urea.
The bespoke approach was the culmination of years of progress in the field of gene editing and marks a huge step toward tailoring rare disease therapies to suit an individual patient’s needs.
This is far from the only gene-editing advance reshaping what’s possible for rare disease treatments. Another CRISPR-based therapy, called EDIT-101, has shown promise in a Phase I/II trial for Leber congenital amaurosis Type 10, a rare inherited condition that causes retinal degeneration, for which there are currently no FDA-approved treatments.
Developed by Editas Medicine (MA, USA), the treatment targets a mutation within the CEP290 gene, working like a pair of ‘molecular scissors’ to essentially cut out the mutation and restore the function of a key gene and protein that enable light-sensing cells to work properly in people with the condition.
In the trial, EDIT-101 improved vision in 79% of participants, demonstrating, preliminarily, its potential in the treatment of this rare disease.
With the potential of gene therapy coming to fruition, this area of medicine, and more importantly, patient outcomes, looks set to be transformed.
Looking ahead, Indurthi told us, “Emerging approaches such as recombinases are future opportunities. These tools expand the range of genetic defects that can potentially be addressed, moving beyond treatment to correction.”
RNA therapies
Another technology showing promise in the treatment of rare diseases is RNA therapies. These work by introducing RNA-based molecules to manipulate the expression and activity of specific target genes and proteins. RNA therapies can be exploited to treat a whole host of diseases that do not respond to conventional drug types, such as orphan diseases.
There are several clinical studies underway for a number of RNA-based therapeutics designed to treat incurable diseases. For rare disease treatment, the most advanced therapies involve small interfering RNA (siRNA)-mediated RNA interference (RNAi) and antisense oligonucleotides (ASOs) – both of which modulate gene expression by binding to target RNA and halting synthesis of pathogenic proteins at the mRNA level.
RNAi uses fragments of double-stranded RNA, siRNAs, to target specific mRNA molecules and recruit the RNA-induced silencing complex to silence them. ASOs, meanwhile, bind to mRNA, causing cells to recognize it as double-stranded and subsequently destroy it.
The first commercially available RNAi therapeutic – Onpattro, developed by Alnylam (Maidenhead, UK) – was approved by the FDA in 2018 for the treatment of a rare disease called hereditary transthyretin amyloidosis with polyneuropathy. The condition is caused by a mutation in the TTR gene, which results in a misfolded protein that builds up in organs. Although Onpattro doesn’t entirely stop production of the mutant protein, it slows it enough to allow the body to clear it, reducing symptoms, which include nerve pain and numbness, fatigue and muscle weakness.
In fact, the first three approved RNAi drugs were all developed at Alnylam, targeting rare, monogenic diseases with targets expressed in the liver. There are currently seven FDA-approved RNAi therapeutics, six of which were discovered by Alnylam.
Several ASOs have also been approved for the treatment of orphan diseases. For example, in 2016, Nusinersen was the first approved disease-modifying therapy for spinal muscular atrophy, a rare genetic neuromuscular disorder. Developed by Ionis Pharmaceuticals (CA, USA) and Biogen (MA, USA), the drug increases the production of SMN2 protein, which compensates for the lack of functional SMN1 protein that is a hallmark of the condition.
More recent ASO drugs offering hope for rare disease patients at the preclinical stage include Arnatar Therapeutics’ (CA, USA) ART4, granted FDA Orphan Drug Designation and Rare Pediatric Disease Designation last year for the treatment of Alagille Syndrome. The drug is designed to address the root cause of the genetic disease – mutations in the JAG1 gene that lead to insufficient protein levels – by upregulating JAG1 protein expression.
In addition, Indurthi commented that “mRNA therapies, particularly those delivered using lipid nanoparticles (LNPs), have revolutionized medicine by enabling both gene editing and protein replacement strategies.” In rare disease research, dozens of mRNA drugs are undergoing clinical trials. These use chemically modified mRNA, introduced into cells via carriers like LNPs, to produce functional proteins that compensate for genetic deficiencies.
For example, preclinical research published in 2024 found that mRNA could be used to correct defective glutathione metabolism in a mouse model of the rare liver disease argininosuccinic aciduria.
These are just some of the ways in which cutting-edge technologies like AI, gene editing and RNA-based methods are pushing rare disease research forward. Although there are many more therapies not mentioned here, current options are a drop in the ocean when you consider the substantial unmet need of millions of orphan disease patients. With any luck, these technologies, and others in future, will help to address this discrepancy by continuing to blaze a trail that advances drug discovery and development for rare diseases.
When asked what the future might look like, Indurthi theorized that the field of rare disease drug discovery “will focus on mRNA‑driven automation, cell‑free workflows, increased use of AI and a more supportive regulatory landscape.”
“These shifts are expected to significantly improve the feasibility of developing treatments for rare and ultra‑rare diseases.”