Understanding rare diseases

Rare diseases affect less than 5 people out of 10,000. However, this still amounts to about 7% of the world’s population, with over 10,000 such conditions. Almost all are genetic in origin, with a few being autoimmune or infectious.

Most such patients undergo a diagnostic and therapeutic odyssey involving extensive and prolonged testing and multiple consultations. Only about 5% of rare diseases are currently treatable, the rest being “orphan diseases.” However, precision medicine could provide an answer to this problem.

Precision medicine and rare diseases

Precision medicine may be described as treatment tailored to the individual patient, based on detailed data about the patient coupled with reasoning back to the root cause at the molecular level. It aims at maximum therapeutic efficacy and minimal drug toxicity for all diseases. It accounts for inter-individual genetic variation that makes each person respond differently to a given disease or its treatment.

Genetic and molecular profiling

Personalized diagnostics

Advances in genomic sequencing, data science, imaging techniques, and genetic diagnosis have made it feasible to study orphan diseases in individual patients or small numbers of patients with a single rare disease. The development of precision medicine added economic and scientific value to investments in this field.

With rare diseases, identification of the molecular pathology, whether an abnormal gene or metabolic pathway, occurs simultaneously with the diagnosis. This should theoretically facilitate treatment since all that is needed is the correction of the single molecular flaw.

The challenge

Traditionally, pharmaceutical research has focused on finding and developing commercially viable treatments that benefit large groups of people, thus excluding people with rare diseases. Few rare diseases have at least one or two approved treatments, leaving a large and untapped market for personalized therapies – mostly gene and cell therapies.

The promise

Whole-genome sequencing and whole-exome sequencing have overcome some important limitations of earlier genomics platforms, enabling the identification of many more pathogenic genetic defects, while RNA sequencing extends its reach.

Still, vast regions of non-coding DNA may contain pathogenic mutations, including regulatory elements, the 5′ untranslated region (5′UTR), and epigenetic modifications. Genome-wide association studies (GWAS), along with transcriptomics, have helped identify genotype-phenotype associations.

Large datasets and data-sharing networks are vital to identifying rare disease gene variants. In the USA, the NIH Undiagnosed Diseases Network (UDN) used an earlier program’s searchable clinical and exome sequencing database to help patients undergoing a diagnostic odyssey reach a diagnosis while gathering valuable data. The UDN assessed over 1,000 patients with one week of hospitalization, diagnosing over 200 very rare diseases and discovering new diseases.

Achieving Rare Disease Research Goals with MGI

This has been extended to UDN International at present, one of several international organizations such as Care-for-Rare, REACT, and IRDIRC that help children with rare diseases.

Tailoring treatments for rare diseases

Customized therapies

Rare disease researchers use gene knock-out and drug repurposing screens in cell lines, tissue models, or animal lines to understand how mutations and drugs affect different cell types, including safety, tolerability, and bioavailability thresholds. This not only identifies diverse drug and gene targets but also allows for optimal treatment design in orphan diseases.

Success stories

1. SMA

The number one cause of death in babies worldwide is spinal muscle atrophy (SMA), caused by defective SMN1 genes leading to dysfunctional survival motor neuron (SMN) protein. This causes motor neuron breakdown and paralysis.

The first approved (2016) therapy for SMA is an ASO called Spinraza (nusinersen), which reduced deaths and the need for ventilation among SMA children. Injected intrathecally, Spinraza rescues motor neurons by promoting the production of functional SMN protein. Gene therapy is in the pipeline, and almost all other therapies are being developed.

2. Other neurological syndromes

Mila Makovec, in Colorado’s Longmont, had Batten’s disease and was rapidly deteriorating when she was put on a personalized nusinersen-like ASO, Milasen, starting in January 2018, to reactivate the single normal copy of the gene that she possessed. Within a month, her seizures were reduced by 50%, but she remains severely disabled.

Susannah Lorem had a rare genetic mutation, KIF1A, causing progressive, debilitating disease. The firm nLorem provided a personalized ASO free for life, starting October 2022.

3. Duchenne

Hereditary muscular disease called Duchenne muscular dystrophy (DMD) causes progressive muscle weakness caused by abnormalities in the dystrophin (a muscle protein) gene. It affects less than one in 6,000 male babies each year.

Potential therapies for DMD include ataluren, a small molecule that causes exon skipping. This could reverse the effect of a nonsense mutation disrupting dystrophin synthesis. That is, it skips a premature stop codon, allowing dystrophin gene transcription.

Sarepta Therapeutics has launched a one-time gene therapy for DMD that enables functional dystrophin synthesis. However, adverse effects, such as acute severe liver injury, myositis, and myocarditis, have been reported during the clinical trials, and a post-marketing trial is going on.

Investigational gene therapies from Pfizer are showing immense promise in DMD, with improvements lasting about 3-5 years.

4. Cystic Fibrosis

Cystic fibrosis (CF) patients rarely live beyond early childhood. Though discovered in 1980, the CFTR gene has 2,000 pathogenic variants, making gene therapy an unsolved challenge in this case. Small-molecule drugs called CFTR modulators have been launched to correct defective CFTR protein function.

An oral drug, Trikafta, combines 3 CFTR modulators, reversing the effects of 178 different CFTR mutations. It may prolong survival in about 90% of CF patients.

The average CF patient lives ten times as long today as in any previous era, with a lifespan extending into the fifties. Notably, this is also because of intensive collaborative research resulting in better airway and nutritional management and improved antibiotic therapy, besides the CFTR modulators.

Challenges and future directions

Overcoming hurdles

Ethical principles still being discussed include the high cost of treating a single individual vs the cost of treating large numbers with readily available drugs. Other questions include the type of evidence needed for drug approval in humans and how to assess its efficacy.

There are nowhere near enough researchers to make custom drugs for all who might want them. And even if there were, who would pay? Unfortunately, that leaves it to families,” says Dr. Steven Joffe, a medical ethicist at the University of Pennsylvania.

Since the Orphan Drug Act of 1983 became law in the United States, research into rare disease therapies has accelerated. The key shift is in value, making rare disease research a booming industry, with the market expected to grow by over 10% every year.

The large market base, plus the incentives from government and private investors such as early access, expanded access, accelerated approval, and extended patent rights programs, coupled with the fact that cell and gene therapies are at the heart of treatment for rare diseases, have powerfully stimulated research and development. In fact, these treatments are readily commercialized despite the small number of patients.

Drug repurposing studies identified the already approved drug epalrestat as a potential therapy for the rare disease PMM2-CDG, a glycosylation disorder. This was followed by a successful trial in the index individual, and larger trials are ongoing.

Rational therapeutic design is a tool to identify molecules that reverse the undesirable impact caused by a pathogenic genetic variant. This helped to identify low-dose ketamine as a potential therapy for a rare disease, ADNP syndrome, part of the autism spectrum disorder.

Precision Medicine in the Era of Rare, 2024

This method includes enzyme replacement in cases of metabolic errors like Gaucher’s disease, antisense oligonucleotides (ASO), tiny corrective DNA bits for spinal muscular atrophy (SMA), small-molecule drugs for cystic fibrosis, and cell or gene-based therapies like stem cell gene therapy for adenosine deaminase deficiency.

Advances in stem cell research help assess individual responses to drugs and identify specific mutations that respond to potentially engineered therapies. This will maximize the odds of obtaining the desired response in clinical practice.

CRISPR gene editing-based therapies to eliminate pathogenic genes with point mutations as in sickle cell disease, and viral gene delivery vectors, are being investigated. Many issues remain to be overcome before their clinical launch.

Using sophisticated data analytics and artificial intelligence (AI) on large datasets of people, either orphan disease patients or related in some way, firms have helped educate and sensitize patients and healthcare providers in the most relevant ways. Such data can help identify high-risk regions or populations, increasing by up to 40% the number of potential patients found.

Using real-world data from large datasets, firms can take advantage of accelerated approval programs for orphan drugs by showing associations between rare diseases and life-threatening outcomes, which could not be proved from the small number of patients available by traditional methods.

Digital technology, including mobile apps, can be leveraged to educate and support patients and caregivers after the diagnosis. It can help HCPs track symptoms and optimize treatment schedules for such patients.

Pharmaceutical companies may invest in such support services in return for real-world information on how their therapies affect the patient. The high costs of treatment, coupled with the need for frequent traveling and doctor appointments, are daunting for many such patients, presenting another opportunity for health investors to step in.

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