The scientific community has been focused on developing treatments for cancer, Alzheimer’s, heart disease, and others that impact much of the population. What about rare diseases that go under the radar? There are numerous conditions that strike a small percentage of people, but in total they affect about 4-6% of the population worldwide.

What is an orphan disease?

Those suffering from rare diseases face multiple challenges. Because of their low occurrence rate and complex clinical presentations, developing therapeutics for these rare diseases is difficult and prohibitively expensive. Thus, research on these diseases receives limited funding, and they are frequently misdiagnosed or undiagnosed. With only a handful of patients available to participate in clinical trials, the drug development process for these conditions also progresses at a slower pace compared to more common diseases.

This means many people living with rare diseases have few, if any, treatment options available. These conditions are often called “orphaned” or “orphan diseases” due to the limited attention they get within the traditional pharmaceutical sector. Fortunately, the FDA’s Orphan Drug Act provides financial and regulatory support necessary for drugmakers to pursue novel treatments for rare diseases more efficiently. It’s an important factor in developing therapies for diseases that would otherwise remain neglected.

Rare disease research trends: ALS, HD, and MG

How is the research landscape changing for rare diseases? We analyzed the CAS Content CollectionTM, the world’s largest human-curated repository of scientific information, to answer this question, and we found that advances in genetic sequencing and drug development are making a positive impact on certain rare diseases. We focused our analysis on three rare diseases — amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and myasthenia gravis (MG). The results show that researchers are making progress in key areas to treat these devastating conditions.

We identified over 530,000 journal and patent publications relating to rare diseases in the CAS Content Collection from 2003-2023. For the purposes of this analysis, we narrowed our focus to ALS, HD, and MG, which show consistent growth in publications over the last five years (see Figure 1).

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Of these diseases, ALS has seen the most research growth since 2014, which coincides with the “Ice Bucket Challenge” event that went viral on social media raising awareness and research funds (see Figure 2). Opinions are divided on the impact of this viral trend, with critics noting the limitations of a short-term influx of funds without a sustainable source of ongoing research support. The overall consensus, however, is that the challenge was beneficial because it provided a much-needed boost to ALS research and demonstrated the potential of innovative fundraising campaigns.

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Challenges to treating ALS, HD, and MG today

The three rare diseases we focused on have different causes and clinical presentations. There is currently no cure for them, and each has uniquely challenging characteristics that have made diagnosis and treatment difficult:

• ALS: Also known as Lou Gehrig’s disease, ALS is a rare progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord that control voluntary muscle movement. Most cases of ALS are sporadic, meaning they occur without a clear family history, while a small percentage are familial (inherited).
  
  ALS is likely a multifactorial disease involving interactions between genetic susceptibility, environmental factors, and various cellular mechanisms leading to motor neuron degeneration and progressive muscle weakness and paralysis. While specific genetic mutations are less common in sporadic ALS compared to familial cases, genome-wide association studies (GWAS) have identified common genetic variants associated with an increased risk of developing ALS. These variants are often found in genes involved in neuronal function, inflammation, and other biological pathways implicated in ALS pathogenesis (see Figure 3).

• HD: Huntington’s disease is caused by a mutation on the HTT gene that encodes the huntingtin protein. HD follows an autosomal dominant pattern of inheritance, meaning that a person who inherits a single copy of the mutant gene will develop the disease. The mutant huntingtin protein disrupts normal cellular functions and results in neuronal dysfunction and death, particularly in the basal ganglia and cerebral cortex of the brain. This disease affects motor capabilities and cognitive function and presents psychiatric symptoms. While the role of HTT in HD is well-established, we identified eight other genes that might play a role in the development and etiology of HD (see Figure 4).

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• MG: Unlike the other two rare diseases we analyzed, MG is an autoimmune disease that affects neuromuscular junctions. With this disease, the body generates antibodies against acetylcholine receptor (AChR) or muscle specific kinase, resulting in the immune system mistakenly attacking receptors on muscle cells, particularly where nerve impulses stimulate muscle contractions.
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  Certain genetic variations or polymorphisms have been associated with an increased risk of developing MG (see Figure 5). However, the inheritance pattern isn’t straightforward, and MG is likely a multifactorial disease involving genetics, environmental triggers, and immune dysregulation.

Can combination therapies offer treatment breakthroughs?

Given the complex nature of these rare diseases and the small number of patients available for clinical trials, researchers are increasingly turning to combinations of previously approved therapies to treat them. These multifaceted approaches, which also leverage advances in genetic and personalized medicine, are showing promise:

• Cell therapies for ALS, HD, and MG
  
  In our analysis of the CAS Content Collection, we found astrocytes and microglial cells most frequently co-occurring in the literature with ALS and HD (see Figure 6). While ALS is traditionally considered a motor neuron disease and HD is a neuronal disorder caused by a mutant protein, emerging evidence suggests that non-neuronal cells, particularly astrocytes, microglia, and other types of neuroglia, play crucial roles in ALS and HD pathogenesis.
  
  Cell therapy is also showing positive results for treating MG, specifically a therapy that works by depleting B cells to reduce disease driving antibodies. Overall, cell therapies can protect neurons from inflammation and promote healthy cell proliferation, all of which are valuable for treating these rare diseases.

• Key drugs in clinical trials:

• RAPA-501, ALS, autologous hybrid TREG/Th2 cells, recruiting, Phase II/III, NCT04220190
• NestaCell, HD, stem cell therapy, active, Phase II/III, NCT04219241
• Descartes-08, MG, CAR-T cells, recruiting, Phase II, NCT04146051

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• Genetic therapies for ALS and HD
  
  Our analysis also revealed that ALS and HD frequently co-occur with gene therapy (see Figure 7). Accordingly, targeting etiologic genes to suppress their toxic impacts have been investigated widely, with the major strategies including: removal or inhibition of abnormally transcribed RNA using miRNA or antisense oligonucleotides (ASOs); degradation of abnormal mRNA using RNAi; decrease or inhibition of mutant proteins using antibodies against misfolded proteins; and/or DNA genome editing with methods such as CRISPR or CRISPR/Cas.
  
  Gene therapies for HD are being explored using genetic material to ramp up the expression of genes whose functions are declined or damaged over the course of the disease. As a monogenic disease, HD is a good target for gene therapy approaches, including the use of programmable endonucleases. A protocol for HTT gene knock-out using a modified Cas9 protein (nickase, Cas9n) has been recently tested with promising results.

• Key drugs in clinical trials:

• AMT-162, ALS, gene therapy agent, recombinant AAVrh10 vector that expresses a miRNA targeting the SOD1 gene, not yet recruiting, Phase I/II, NCT06100276
• AB-1001, HD, CYP46A1 gene therapy agents, active Phase I/II, NCT05541627

• Drug repurposing to speed up treatment options
  
  Drug repurposing, also known as drug repositioning, is critically important for addressing rare diseases. The safety profiles of existing drugs are already well understood, which means there is less time and cost required to bring them into clinical usage for a different disease than their original target. Leveraging existing data is also a practical way to expedite the discovery of new treatments. For patients suffering from rare diseases, faster access to effective treatments can be a major improvement in their quality of life.
  
  As seen in Figure 7, anti-Alzheimer’s and anti-Parkinson’s drugs co-occur with ALS and HD. These neurodegenerative diseases share pathological features such as protein aggregation and neuroinflammation, making this crossover a promising area of research.
  
  Relating to MG, anti-rheumatic drugs for conditions such as rheumatoid arthritis are being explored. The use of these drugs highlights the commonality in immune system dysregulation across different autoimmune diseases, suggesting that immune-modulating therapies might have broader applications than initially intended.

Key drugs to watch:

• Ropinirole, used to treat Parkinson’s and recently has shown potential to slow the progression of ALS
• Rituximab, originally developed for non-Hodgkin's lymphoma, used to treat MG‍
• Small molecules are the most-explored drugs in developments for ALS and MG
• Currently, small molecule drugs make up 50% of preclinical drug candidates for ALS and MG and 10% for HD (see Figure 8). Because of their low molecular weight (generally less than 900 daltons), small molecules can penetrate cell membranes and target intracellular pathways and processes, which are often implicated in diseases like ALS and MG. They can also cross the blood-brain barrier to treat neurodegenerative diseases like ALS.
  
  Due to their versatility, cost-effectiveness, and potential for combination therapies, small molecule drugs are an attractive and practical choice for addressing the complex pathologies of these rare diseases, and we’re seeing many candidates in clinical trials today:

Drugs in clinical trials:

• FB1006 was fully discovered and developed using AI, developed to treat ALS, NCT05923905.
• Ibudilast was developed as part of HEALEY ALS Platform trial (NCT04297683) and received fast track and orphan drug designations from the FDA in 2016.
• SAGE-718 is currently recruiting for Phase II/Phase III clinical trials for treating HD, NCT05655520.
• ALXN2050 is currently in active Phase II clinical trial for treating MG, NCT05218096.

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The future of rare disease research

ALS, HD, and MG each represent a unique manifestation of genetic, environmental, or infectious factors, often with distinct clinical presentations and treatment challenges. Despite these persistent roadblocks, there is reason for optimism due to advances in genomics, molecular biology, and precision medicine. From cutting-edge gene therapies to innovative drug repurposing to new small molecule drugs in clinical trials, researchers are exploring diverse modalities to address the unmet medical needs of individuals with rare diseases.

For deeper insight on the research landscape of rare diseases, see this recent CAS Insights report.

Key data in this article as well as Figures 1-8 are extracted from Iyer K, Tenchov R, Sasso JM, Ralhan K, Jotshi J, Polshakov D, Maind A, Zhou QA. Rare diseases: Insights from landscape analysis of current research, spotlighting amyotrophic lateral sclerosis, Huntington’s disease, and myasthenia gravis. ChemRxiv. 2024; 10.26434/chemrxiv-2024-rkqvt.

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