Rare diseases represent a diverse group of disorders (~11,000), each one affecting a small fraction of the population. Despite their individual rarity, rare diseases impact ~400 million people globally and pose significant challenges for patients, healthcare providers, and drug developers alike. Historically, the development of rare-disease treatments has been slow and often neglected because of limited pathological understanding, small patient populations, and high costs associated with research and development (R&D). However, recent years have witnessed a revolution in rare-disease research, driven by technology advancements, increased collaboration, and a growing recognition of unmet patient needs.

Advancements in Rare-Disease Research

Rare-disease researchers have made remarkable progress by using innovative technologies such as artificial intelligence (AI) and establishing collaborative initiatives around the globe.

Genomics and Precision Medicine: Next-generation sequencing (NGS) has transformed genomics by enabling swift sequencing of entire genomes and pinpointing genetic mutations that drive rare diseases. With decreasing DNA-sequencing costs, genome sequencing (GS) is emerging as a first-line investigation that can provide molecular diagnoses in individuals with rare diseases. GS detects a wide array of genetic abnormalities even in noncoding regions, generating extensive data that can be reanalyzed periodically. Regularly reexamining GS data can help scientists to enhance diagnostic yields, given the continuing discovery of novel disease-causing genes and ongoing improvements in bioinformatic tools, interpretation methods, and genetic-variation databases. As more rare-disease patients receive molecular diagnoses, targeted drug development and medication repurposing will gain momentum. Thus, refined diagnostics and enhanced orphan-drug development will improve outcomes for precision medicine and individuals with rare diseases (1).

Biomolecular Technologies: In addition to genomics tools, complementary -omics technologies now are implemented routinely in molecular diagnostic workflows for diagnosing rare diseases and providing insights into their molecular mechanisms. By integrating genomics, proteomics, and metabolomics data into knowledge graphs such as the Clinical Knowledge Graph (2), researchers can precisely identify affected metabolic pathways and potential biomarkers and even propose therapeutic strategies (3).

Cell and Gene Therapy (CGT): 80% of rare diseases are genetic, so CGTs hold great promise for their treatment, especially those resulting from single-gene defects (monogenic). Advances in gene-editing technologies, such as those based on clustered regularly interspaced palindromic repeats (CRISPR) and associated protein 9 (Cas9), enable precise correction of disease-causing mutations in patient cells, offering potential cures for previously untreatable conditions (4).

Since 2017, the US Food and Drug Administration (FDA) has approved 35 CGTs, half of which have received orphan-drug designations (5). Moreover, scientists are using induced pluripotent stem cells (iPSCs) derived from patient cells to model rare diseases in the laboratory, facilitating drug discovery and personalized medicine approaches (6).

Drug Repurposing: Drug repurposing involves the identification of new therapeutic uses for existing drugs approved for other indications. Compared with de novo drug development, such an approach offers cost-effective strategies for orphan-drug development because repurposed drugs have already undergone extensive preclinical and clinical testing for safety and efficacy. By leveraging large-scale data mining and machine learning (ML) algorithms, researchers have developed tools such as the Open Targets Platform and Biovista’s COSS discovery system, which can summarize evidence from literature and calculate association scores between diseases and drugs or drug targets (7).

Patient Registries and Natural-History Studies: The low prevalence of rare diseases results in scarce, disperse patient data. Even detailed studies often lack information on the pathology, symptoms, and disease progression for such diseases. Patient registries and natural-history studies — using observational study methods to gather uniform data and assess specified outcomes for rare-disease populations — serve as tools to work around small population sizes in research and clinical trials. Due to the relentless work of patient advocacy groups (PAGs), the popularity of rare-disease patient registries has risen, with over 800 registries listed in a December 2021 Orphanet report (8). Patient registries and natural-history studies not only facilitate patient recruitment for clinical trials, but also provide valuable insights into disease progression and variability and treatment outcomes. By better understanding the natural history of rare diseases, researchers can develop more informative clinical trials and effective therapies.

Challenges in Orphan-Drug Development

Despite advances in research, 95% of rare diseases still do not have treatment options because orphan drug-development continues to face significant challenges.

Genetically Heterogeneous Patients: One of the major hurdles in orphan-drug development is the small size of patient populations affected by rare diseases. Limited patient numbers dispersed in different geographical locations make it difficult to recruit participants for clinical trials, leading to slower trial enrollment, increased costs, and challenges in demonstrating statistical significance. Additionally, the heterogeneity of rare diseases can complicate clinical-trial design and interpretation further because patients may present diverse clinical phenotypes and genetic backgrounds.

Lack of Disease Understanding: Many rare diseases are poorly understood in terms of their underlying pathophysiology and natural history. Limited understanding hinders target identification, biomarker development, and patient-stratification strategies. Furthermore, the lack of disease-specific endpoints and validated outcome measures complicates the design and interpretation of clinical trials, leading to delays in drug development and regulatory approval.

High Development Costs: Orphan-drug development incurs high R&D costs because of limited patient populations and the need for specialized expertise, resources, and infrastructure. The high cost, coupled with the uncertainty of commercial success, presents a significant financial risk for pharmaceutical companies and investors. As a result, many orphan-drug candidates never progress beyond the preclinical stage or early-phase clinical trials due to lack of funding or commercial viability.

Regulatory and Reimbursement Challenges: Regulatory approval and reimbursement for orphan drugs pose unique challenges compared with those for conventional pharmaceuticals. Although regulatory agencies offer expedited pathways — e.g., the US Orphan Drug Act and the EU Orphan Medicinal Products Regulation — to incentivize rare-disease drug development, the requirements for demonstrating safety and efficacy remain rigorous. Moreover, securing funds can be difficult due to the high cost of orphan drugs and the uncertainty surrounding their long-term clinical benefits.

Collaborative Approaches and Future Directions

Addressing the challenges of orphan-drug development requires a concerted effort from various stakeholders, including researchers, clinicians, pharmaceutical companies, regulatory agencies, PAGs, and policymakers. The following key initiatives can guide collaborative approaches and innovative strategies to accelerate progress in the rare-disease field.

Cross-Border Collaborations: Each rare disease affects a small population dispersed globally. Therefore, cross-border collaboration in research could enhance quality of life for individuals affected by rare diseases. Initiatives such as the E-Rare program and the International Rare Diseases Research Consortium (IRDiRC) coordinate the efforts of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations to maximize the collective impact of investments in rare-disease research. The FDA’s recent Collaboration on Gene Therapies Global Pilot (CoGenT Global) seeks to promote “regulatory convergence” across jurisdictions by reducing costs and review times while enhancing the commercial viability of CGTs for rare-disease treatment (9). Because most of the world’s population resides in Asia, Africa, and the Middle East, industry and regulatory collaboration should increase with companies and health authorities from those regions.

Public–Private Partnerships: Collaborative initiatives among academia, industry, and government agencies can help to leverage complementary expertise, resources, and funding for accelerating-orphan drug development. Public–private partnerships, such as the US National Institutes of Health (NIH) Therapeutics for Rare and Neglected Diseases (TRND) program and the Bespoke Gene Therapy Consortium (BGTC), support precompetitive research, drug discovery, and early phase clinical development for rare diseases. More such collaborations are needed to derisk and accelerate rare-disease drug development.

Data Sharing and Open Science: Sharing preclinical and clinical data openly can enhance collaboration, reproducibility, and knowledge dissemination in rare-disease research. Initiatives such as the Global Alliance for Genomics and Health (GA4GH) and FAIR (findable, accessible, interoperable, and reusable) principles promote data sharing and interoperability across research communities, facilitating discovery and validation of drug targets and biomarkers.

Inclusive, Patient-Centered Drug Development: Ethnically diverse patients must be involved throughout the drug-development process to ensure that their perspectives, needs, and preferences are considered from the outset. Patient input should inform every stage of drug development, from research prioritization and study design to endpoint selection and regulatory approval. Researchers should integrate patient-reported outcomes (PROs) and patient-centered endpoints into clinical trials to capture meaningful treatment effects. Through active engagement with patients, advocacy groups, and community stakeholders, drug developers can gain invaluable insights into the experiences of individuals with rare diseases, leading to more effective treatments and improved health outcomes for those affected by such conditions.

Leveraging AI: AI holds immense potential in advancing rare-disease research. AI algorithms can analyze large amounts of heterogeneous data to identify novel disease mechanisms, biomarkers, and therapeutic targets. AI use in research can facilitate precise patient stratification and tailored treatments. AI tools also can address challenges in patient recruitment and ethnic diversity by integrating multiple data sources to align patients with complex inclusion criteria. AI has the potential to improve patient selection by disseminating information to a broad cross-section of potential participants through public clinical-trial platforms, promoting fairer access to trials.

Decentralized Clinical Trials (DCTs): DCTs offer a paradigm shift in clinical trial execution by reducing logistical burdens and enhancing patient access and participation (10). For rare diseases, which often involve geographically dispersed patient populations, DCTs can overcome recruitment challenges and improve patient retention. Moreover, remote monitoring and data collection enabled by digital health technologies can streamline trial operations and accelerate data analysis, expediting the development of orphan drugs and improving outcomes for individuals with rare diseases.

Governments, industry leaders, and PAGs must collaborate to allocate adequate resources, foster international collaboration, and streamline regulatory processes for rare-disease drug development. Groups such as the Indo US Organization for Rare Diseases (IndoUSrare) play a pivotal role in initiating collaborations and providing a platform for crucial discussions on rare diseases and orphan-drug development, aiming for equitable healthcare on a global scale.

References

1 Might M, Crouse AB. Why Rare Disease Needs Precision Medicine — and Precision Medicine Needs Rare Disease. Cell Rep. Med. 3(2) 2022: 100530; https://doi.org/10.1016/j.xcrm.2022.100530.

2 Santos A, et al. A Knowledge Graph To Interpret Clinical Proteomics Data. Nat. Biotechnol. 40(5) 2022: 692–702; https://doi.org/10.1038/s41587-021-01145-6.

3 Smirnov D, Konstantinovskiy N, Prokisch H. Integrative Omics Approaches To Advance Rare Disease Diagnostics. J. Inherit. Metab. Dis. 46(5) 2023: 824–838; https://doi.org/10.1002/jimd.12663.

4 Papaioannou I, Owen JS, Yáñez-Muñoz RJ. Clinical Applications of Gene Therapy for Rare Diseases: A Review. Int. J. Exp. Pathol. 104(4) 2023: 154–176; https://doi.org/10.1111/iep.12478.

5 Approved Cellular and Gene Therapy Products. Center for Biologics Evaluation and Research: Silver Spring, MD, 2024; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

6 Bombieri C, et al. Advanced Cellular Models for Rare Disease Study: Exploring Neural, Muscle, and Skeletal Organoids. Int. J. Mol. Sci. 25(2) 2024: 1014; https://doi.org/10.3390/ijms25021014.

7 Jonker AH, et al. Drug Repurposing for Rare: Progress and Opportunities for the Rare Disease Community. Front. Med. 11, 2024: 1352803; https://doi.org/10.3389/fmed.2024.1352803.

8 Hageman IC, et al. A Systematic Overview of Rare Disease Patient Registries: Challenges in Design, Quality Management, and Maintenance. Orphanet J. Rare Dis. 18(1) 2023: 106; https://doi.org/10.1186/s13023-023-02719-0.

9 Eglovitch JS. FDA Eyes Collaborative Review Pilot for Gene Therapies. Regulatory Focus, 12 January 2024; https://www.raps.org/news-and-articles/news-articles/2024/1/fda-eyes-collaborative-review-pilot-for-gene-thera.

10 Ghadessi M, et al. Decentralized Clinical Trials and Rare Diseases: A Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG) Perspective. Orphanet J. Rare Dis. 18(1) 2023: 79; https://doi.org/10.1186/s13023-023-02693-7.

Deepti Dubey, PhD, is a scientific writer at IndoUSrare (https://IndoUSrare.org), and Harsha K. Rajasimha, PhD, is the founder of IndoUSrare, as well as the founder and chief executive officer (CEO) of Jeeva Clinical Trials (https://jeevatrials.com); [email protected].