Offering Fresh Hope: Game-Changing Drug Discoveries for Rare Diseases

Rare diseases affect a very small portion of the population, typically less than 1 in 2,000 people. Around 80% of rare diseases have a genetic origin, and are often biologically complex, meaning that they are not very commercially attractive to the pharmaceutical industry.¹

But the people living with these life limiting conditions need treatment to ease or treat their symptoms, so how are drugs developed for such conditions? Patient-led organizations have stepped in to fund the costly, early-stage academic development of treatments for rare diseases.

Two such examples are the AT Society and Cystic Fibrosis Trust, both of whom are supporting researchers on the frontline of developing new drugs to treat the symptoms of ataxia telangiectasia (AT) and cystic fibrosis (CF).

Combined strategies for patient-tailored treatment for AT

There are an estimated 200 cases of AT in the UK; this rare, inherited condition is complex and life limiting, and leaves children practically wheelchair-bound by the age of 10. It is sometimes referred to as a “multi-system” disorder because it affects several different organs or systems within the body, but there is a lot of variability between individuals and no two people with AT will have the exact same symptoms.^2,3

Symptoms are not immediately apparent at birth; they tend to develop slowly over time until the age of seven or eight when they worsen more quickly. Ataxia or lack of coordination is usually the first to appear, followed by difficulties with speech and swallowing, and then fatigue, low weight, and slow growth. Around two-thirds of individuals will have a weakened immune system, making them more susceptible to frequent coughs, colds, and infections of the throat, ear, sinuses, and sometimes lungs. There is also a greatly increased risk of cancer; roughly 25% of people with AT will develop cancer, usually lymphomas or leukemia in children, and solid tumors such as breast cancer and cancer of the esophagus in adults.³

AT is caused by a mutation in a single gene—the ATM gene, which is involved in DNA repair, cell division, and maintaining genetic stability. The mutation prevents the ATM protein from being produced. Understanding how this deficit causes the different symptoms of AT would make it easier to find drugs to intervene in these processes.⁴

Gene therapy might be the most obvious choice, but the ATM gene is a quite large—66 exons and more than 150 kb of DNA —making it unsuitable for traditional gene therapy using viruses. To overcome this issue, Dr. James Dixon and his research group at the University of Nottingham Biodiscovery Institute have been focusing on advanced non-viral delivery technologies, developing peptide-based nanoparticles that can safely and efficiently deliver large therapeutic genes and gene editing tools into hard-to-reach tissues like the brain.

“This is particularly important for AT, where neurodegeneration drives many of the most devastating symptoms and where conventional viral gene therapies are unsuitable due to the size of the ATM gene and safety concerns,” explained Dixon. “By combining innovative nanoparticle chemistry with state-of-the-art gene editing approaches, we aim to restore ATM activity either by correcting faulty genes or by providing new, functional copies in affected cells.”

Dixon’s work, which includes collaborators from the UK, USA, and EU, is helping to develop new drugs for AT “by creating a realistic and scalable pathway to a permanent, disease-modifying therapy rather than symptomatic treatment. Our platform is designed to be flexible, allowing repeated or single-dose administration, low immunogenicity, and precise control over where and how therapeutic genes act.”

And the technology doesn’t just apply to AT; it can be adapted for other genetic and neurodegenerative disorders, accelerating the broader development of next-generation nucleic-acid medicines. “Ultimately, this research lays the groundwork for first-in-human trials and offers real hope of long-term benefit, improved quality of life, and potentially a cure for people living with AT,” Dixon added.

Dixon’s team are also developing antisense oligonucleotide (ASO) strategies as a complementary and alternative therapeutic route. “ASOs offer a powerful way to modulate ATM expression or correct specific splicing defects without permanently altering the genome,” Dixon said. “This approach could be especially valuable for patients with particular mutation classes or as an earlier-stage intervention while gene therapy approaches continue to mature. Importantly, the same brain-penetrating nanoparticle technologies we have developed for gene delivery can also be adapted to deliver ASOs efficiently to the central nervous system, creating a unified delivery platform for multiple therapeutic modalities.”

Dixon believes this combined strategy could offer flexible, patient-tailored treatments for AT. “Permanent ATM gene augmentation or editing offers the possibility of a one-off, lifelong correction, while ASO-based therapies provide a reversible, adjustable alternative that may reach the clinic more rapidly for some patients.”

By developing and validating both approaches in parallel, the research “maximizes the chances of delivering effective new drugs for AT and ensures that emerging therapies can be matched to patient need, disease stage, and long-term safety considerations,” Dixon said.

And the work could make “a profound difference” to the lives of those with AT by “addressing the disease at its root cause rather than only managing symptoms,” Dixon added. “By restoring ATM function in affected cells—particularly in the brain, where neurodegeneration drives loss of movement, speech, and independence—these approaches aim to slow, halt, or even prevent the progression of the most debilitating aspects of the condition.”

If successful, this could mean children with AT retain their mobility, coordination, and communication for longer, which would improve independence, education, and social participation. In the longer term, Dixon believes therapies based on ATM gene replacement, gene editing, or ASO could reduce the need for repeated hospital visits and invasive supportive care by offering durable or even permanent correction with a single or limited number of treatments.

“This would not only improve quality of life for patients, but also significantly reduce the emotional, physical, and financial burden on families and caregivers,” Dixon said. “Importantly, by developing multiple complementary treatment strategies, this work increases the likelihood that effective therapies can be tailored to different patients, disease stages, and mutation types—bringing real hope of longer, healthier lives for people living with AT.”

Small molecule drugs for CF

CF is well-known—it’s the most common genetic disease in the Caucasian population—but is considered rare, affecting just 10,000 people in the UK. Around one in 25 people carry a faulty CF gene, usually without knowing, and if two carriers have a child, that child has a one-in-four chance of having CF.^5,6

“CF is an inherited autosomal recessive condition,” explained Dr. Maya Desai, a retired consultant respiratory pediatrician at Birmingham Women's and Children's NHS Foundation Trust. “The most common CF-causing genetic variants occur in white populations although CF can be found in almost every other ethnicity.”

CF is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and the protein it produces; over 2,000 specific gene mutations have been identified so far.⁵

Defects in the gene “result in chloride channel dysfunction in many cells of the human body,” said Desai. This causes a thick, sticky mucus to collect in the lungs and digestive system of individuals with CF. “Main manifestations are recurrent chest infections and the progression to bronchiectasis and pancreatic insufficiency which results in failure to thrive and malnutrition,” Desai added.

Most people are treated with tablets or treatments focused on preventing and treating the results of the defect, but more recently therapies have targeted the faulty CFTR protein and its production.^5,6

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The CFTR protein is an attractive therapeutic target, and small molecule CFTR modulators like Kaftrio® (ivacaftor/tezacaftor/elexacaftor), Symkevi® (tezacaftor/ivacaftor), and Orkambi® (lumacaftor/ivacaftor) have been developed to target the underlying cause of CF by helping the CFTR protein work more effectively. The modulators help regulate the flow of water and chloride in and out of cells, and when chloride moves more normally, mucus in the lungs and other organs becomes thinner and less sticky.^7,8

 “Small molecule drugs interact with the process of CF gene expression and protein production to either increase gene expression or improve the protein folding and function. Current modulators are either CFTR correctors or potentiators, usually given in combination. By increasing the amount of functioning protein available, either by increasing production or improving its function, the chloride channel can work more normally as it does in healthy people,” Desai said.

These modulators were developed through a long process of developing candidate molecules and refining their properties using in vitro models, Desai said. Firstly, functional assays that examine chloride channel activity were developed to allow scientists to evaluate new treatments. Then, high-throughput screening rapidly tested thousands of compounds in a short space of time in search of potential therapeutic “hits,” which can be further developed for clinical use.⁵

There are currently five CFTR modulators approved for use by the NHS in England and these treatments work for around 90% of people with CF, but research is aimed at developing new treatments for the remaining 10%.^5,8

But for now, standard care involves “antibiotics for infections, chest physiotherapy, nebulized mucolytics, pancreatic enzyme supplements, vitamins, hospital admissions, multidisciplinary care delivered in specialist centers,” Desai said. “The modulators are given in addition. In time, some elements of standard care will be reduced.”

Offering hope

Living with a rare disease is confusing, worrying, and exhausting. These diseases are complex, and it’s not that they are poorly understood, rather that treatments and cures might not be as readily available as they are for other diseases.

Drug development can be costly and lengthy, and pharmaceutical companies lean more towards drugs that are profitable and will benefit a greater number of individuals. However, treatments for rare diseases should not be overlooked.

Thanks to charities like the AT Society and Cystic Fibrosis Trust, vital research into what causes these diseases and how their progression can be slowed or symptoms lessened can continue, offering hope for patients that one day, a drug to treat their rare disease might become a reality.