First described in 1882 by French physician Philippe Gaucher, is a lysosomal storage disease that causes a fatty substance called glucocerebroside to build-up inside a patient’s cells, most commonly in the liver, spleen, and bone marrow. Over time, this abundance of glucocerebroside begins to damage the organs and tissues around it.

Symptoms vary from person-to-person, but, if left untreated, the disease can cause enlarged organs, anaemia, and painful bone complications, with severe cases sometimes requiring surgical intervention.

By the 1960s, treatment for the disease still largely focused around managing patient symptoms. Unsatisfied with this approach, US physician-scientist Dr Roscoe Brady and his colleagues at the US National Institutes of Health (NIH) set out to identify exactly what was causing the build up of glucocerebroside in Gaucher disease patients. Their hope was that if they could find the culprit, they could develop a therapy to target it.

The big breakthrough can in 1966, when Brady’s team discovered that patients with Gaucher disease were unable to produce enough working glucocerebrosidase (GCase), the enzyme responsible for breaking down glucocerebroside.

Emboldened by the promise of a potential therapeutic target, Brady theorised that, if patients could not produce enough functional GCase themselves, perhaps the missing enzyme could be supplied as a treatment. Thus, the concept of enzyme replacement therapy (ERT) was born. However, it quickly became clear that turning that idea into a viable medicine, would be a lengthy and challenging process.

Initially, Brady's team focused on extracting and purifying the enzyme from human placenta. Early experiments in the 1970s were promising, demonstrating that intravenous administration could reduce glucocerebroside accumulation in patients' livers. But there was a problem. The enzyme was not being taken up efficiently by macrophages, the cells in which the lipid accumulates.

After decades of trial and error, researchers were able to modify GCase to improve its uptake into these cells. The breakthrough brought the treatment closer to clinical success, with a 1990 study reporting improvements across multiple measures in a child with Gaucher disease. US biotech company, Genzyme (which was acquired by Sanofi in 2011) subsequently partnered with the NIH to develop the enzyme for larger-scale production and clinical testing.

In a trial involving 12 people with moderate-to-severe Type 1 Gaucher disease, all participants showed dramatic improvements. The results supported the FDA's 1991 approval of alglucerase (Ceredase), the first ERT approved for a lysosomal storage disorder. While no longer in circulation, the drug helped open the door for ERT to become a routine treatment option, and challenged the notion of an “untreatable” rare disease.

Almost a century after the condition was first independently identified by German neurologist Johann Hoffmann and Austrian neurologist Guido Werdnig, the underlying cause of SMA still remained elusive. That changed in 1995, when a research group led by French geneticist Judith Melki discovered that the cause of approximately 95% of SMA cases could be traced back to the survival motor neuron 1 (SMN1) gene. SMN1 is responsible for producing the SMN protein, but in patients with SMA this gene is either damaged or missing.

The discovery of a second gene – aptly named, SNM2 – offered a potential route to treatment. Four years after Melki’s initial discovery, in 1999, researchers Dr Umrao Monani and Dr Chris Lorson identified the RNA splicing error causing the seventh exon in SMN2 to be skipped in patients with SMA.

Researchers quickly began focusing on how to fix the RNA splicing problem. Following research supported by patient organisation Cure SMA and further development at Cold Spring Harbor Laboratory, Ionis Pharmaceuticals and Biogen began development of nusinersen (Spinraza), an antisense oligonucleotide that alters SMN2 processing to increase production of functional protein. The FDA approved Spinraza in December 2016, making it the first disease-modifying treatment for SMA.

The success of Spinraza opened the door for other therapies to enter the market. In 2019, the FDA approved onasemnogene abeparvovec (Zolgensma), a gene addition therapy developed by AveXis, which was acquired by Novartis in 2018. However, rather than modifying SMN2, this treatment delivers a functional copy of the SMN1 gene. Roche's risdiplam (Evrysdi), an oral small molecule that also targets SMN2 processing, received FDA approval in 2020.

In four short years, researchers had given patients three distinct therapeutic approaches they had been waiting decades to receive.

The story of Luxturna began in 1992, when the husband-and-wife team of molecular biologist Jean Bennett and ophthalmologist Albert Maguire at the University of Pennsylvania began investigating gene transfer to retinal cells. At the time, the field was still in its infancy. Researchers were only beginning to identify the genetic causes of inherited retinal diseases and questions remained around the safety, delivery, and durability of gene therapy.

Their research focused on Leber congenital amaurosis, a rare inherited retinal condition that causes severe visual impairment, often progressing to blindness. In 1992, the team began experimenting with gene delivery to retinal cells, initially using recombinant adenoviruses before moving to adeno-associated virus (AAV) vectors, which offered a more favourable safety and delivery profile.

As it turned out, to unlock the secrets of the RPE65 mutation, researchers would have to turn to a familiar aide: man’s best friend, the humble dog. Working with veterinary and gene therapy researchers, Bennett and Maguire treated three puppies using a functional copy of the RPE65 gene delivered directly into the retina. The results were astounding. Dogs that had previously struggled to navigate their surroundings began playing together and moving around without bumping into objects.

The next challenge was translating these findings into human trials. Alongside physician-scientist Katherine High, the team developed a clinical programme that required overcoming several regulatory and technical hurdles, including establishing a meaningful way to measure improvements in functional vision. One solution was an obstacle course designed to assess patients' ability to navigate in different lighting conditions.

Clinical trials demonstrated meaningful improvements in patients' ability to navigate their surroundings, with some describing seeing their children's faces clearly for the first time.

The FDA approved voretigene neparvovec (Luxturna) in December 2017, followed by European approval in 2018. The milestone provided the first clear demonstration that gene therapy could restore function in people with an inherited retinal disease, helping establish a pathway for further genetic medicines.

Although not referenced by name, descriptions of bleeding conditions very similar to haemophilia can be found as early as the 2^nd Century BC in a collection of Jewish rabbinical writings on laws and traditions known as the Babylonian Talmud.

Due to the prevalence of the disease among intermingling royal households (most notably through Queen Victoria), the disease was dubbed “the royal disease”, but – as with most diseases – the genetic mutation didn’t discriminate the royal from the subject; any mutation-carrying mother, regardless of status, could pass down the disorder to their child.

The first recorded treatment of haemophilia was reported in 1840 in The Lancet. After a relatively simple procedure to correct strabismus (a squint), London surgeon Samuel Armstrong Lane found that his patient, 11-year-old George Firmin was bleeding… a lot. According to historical accounts, Firmin’s wound continued to bleed for six days after the operation, despite repeated attempts to remedy the issue.

Finally, Lane resolved that the best course of action was to perform a blood transfusion. The procedure was a resounding success, and Firmin fully recovered within three weeks.

Up until the late 1960s, whole blood or fresh plasma transfusions remained the standard of care. But there was a big problem with this method. Each bag of plasma only contained a very small amount of the necessary clotting factor VIII, which meant that clinicians had to administer huge volumes of it to effectively treat the patient. Not only was this unpleasant, it meant that transfusion had to be performed in a hospital setting and sourcing enough plasma to treat each patient was no easy task.

In 1965, Dr Judith Pool, a researcher at Stanford, observed that thawed fresh frozen plasma was rich in factor VIII. She published a paper on her findings, which she dubbed cryoprecipitate, writing that, because the smaller volumes of thawed plasma contained more potent levels of factor VIII, it could substantially reduce the amount needed to control bleeding disorders, such as haemophilia; an idea that would dramatically improve the availability of treatment.

By the 1970s, freeze-dried powdered concentrates containing factor VIII and IX became widely available. These concentrates were a welcome change for patients, who could now store and “self-infuse” factor products from the comfort of their own home.

Technological advancements have since introduced a new generation of recombinant products – with and without inhibitors – designed to improve the safety and efficacy of treatment. In 2017, the novel agent, emicizumab (Hemlibra), from Hoffman-La Roche, was granted FDA approval for the treatment of haemophilia A with or without inhibitors. A few years later, Pfizer’s marstacimab (Hympavzi) was approved in October 2024 by the FDA for prophylaxis in adult and adolescent patients with haemophilia A or B without inhibitors.

Patisiran was developed as a treatment for hereditary transthyretin amyloidosis (hATTR), a progressive condition caused by mutations in the transthyretin (TTR) gene. The liver produces most circulating TTR, but, in people with hATTR, mutated proteins can accumulate as amyloid deposits, most commonly in the heart and peripheral nerves. This can result in neuropathy and cardiomyopathy, with potentially life-threatening consequences for patients.

Before the arrival of gene-silencing medicines, treatment options were limited. Liver transplantation could reduce production of the abnormal protein, but the emergence of RNA interference (RNAi) offered researchers a very different approach: stopping the disease-causing protein from being produced in the first place.

RNAi is a naturally occurring cellular process that regulates gene expression by degrading specific messenger RNA (mRNA) molecules before they can be translated into proteins. Researchers at Alnylam Pharmaceuticals sought to harness this mechanism using small interfering RNA (siRNA), a natural cellular mechanism that breaks down specific messenger RNA molecules and prevents them from being used to produce proteins.

The result was patisiran. The siRNA was packaged inside a lipid nanoparticle, allowing it to reach liver cells, where most circulating TTR is produced. Once inside, it triggers the degradation of TTR messenger RNA, reducing production of both normal and mutant forms of the protein.

Clinical development demonstrated the potential of the approach. In the pivotal Phase 3 APOLLO trial, patisiran was evaluated in people with hATTR-related polyneuropathy. The results showed improvements in neuropathy-related measures and quality of life compared with placebo, providing evidence that silencing TTR production could meaningfully alter the disease's course.

The FDA approved Onpattro in August 2018 for adults with hATTR-related polyneuropathy. It was the first medicine to demonstrate that RNAi could be translated into an approved therapeutic.

The achievement established an entirely new approach to drug development. Subsequent approvals of other RNAi medicines for rare genetic conditions demonstrated that the technology could be adapted to target different disease-causing proteins, bringing the prospect of gene silencing into a much wider range of therapeutic areas.