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Moving Towards the Next Era in Rare Disease Therapeutics

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Despite progress made in recent years, many rare disease patients still face a diagnostic odyssey and have access to few, if any, effective treatments.

In this two-part interview series, Technology Networks explores some of the reasons behind the difficulties diagnosing and treating rare diseases, and finds out more about recent developments to improve options for patients.

For our second interview, we spoke to four experts from PerkinElmer to learn about some of the current efforts to accelerate drug discovery for rare diseases, including the potential that gene therapies could offer. The role that advances in technologies such as CRISPR and RNAi are playing in increasing our understanding of rare diseases is also discussed.

Anna MacDonald (AM): Very few rare diseases currently have an approved treatment option. What are the reasons for this? 

Amanda Jones (AJ): Although rare diseases effect an estimated 350 million people worldwide, they comprise approximately 7,000 different conditions ranging from neurological disorders, infectious diseases and rare cancers to genetic syndromes. For an individual with a rare condition, getting a diagnosis and treatment can be a challenge since disease presentation is often very varied and physician experience is limited. For therapeutic development this equates to limited sample sizes for clinical development, making larger clinical trials protracted, if not impossible.

In addition to the practical challenges of running clinical trials on small populations with varied pathology, the fact that there is limited opportunity for patient treatment means the financial reward makes rare diseases less attractive for drug companies to embark on risky and expensive development, thus the term “orphan diseases”.

Kyoko Kushiro (KK): Though some literature approximates 80% of rare diseases to have a genetic origin and most of these to be monogenic in origin, most disorders have complex consequences at a phenotypic level (systemic as well as local/protein interactions), making both the identification and establishment of a threshold for therapeutic efficacy against therapeutic targets in the canonical sense of drug discovery difficult.

Another aspect that is an extension to the lack of affected individuals globally to recruit into clinical trials, which is that for some rare diseases, the effective window for the therapeutic treatment may be  short (e.g., a childhood rare disease whose phenotypic consequence could start at gestation or within the first 1–2 years from birth or a sporadic/non-genetic case of rare disease) or diseases with different degrees of penetrance of some disorders, which can also complicate some of the requirements to provide justification for therapy approval by regulatory bodies. This is also a point if there is a lack of public awareness around the rare disease or a reliable means to access a companion diagnostics/discovery of reliable biomarkers for some disorders.

AM: Can you tell us about current efforts to accelerate drug discovery for rare diseases?

AJ: In recognition of the risk-reward imbalance, in 1983, the orphan drug act (ODA) created a series of incentives to help attract R&D investment. These include market exclusivities for approved orphan products, tax credits towards clinical trial costs and research grants.


Often rare diseases benefit from fast-track approval programs for breakthrough therapies, designed by regulators to speed new drugs to market.

New generation of AI led drug discovery, that is hypothesis free and highly scalable is helping to understand the complex biological mechanisms that drive rare diseases.

Providing public, clinicians and researchers access to the Genetic and Rare Diseases Information Centre (GARD) aid trial recruitment and access to field specialists.

AM: What are the advantages that gene therapies could offer to rare disease patients? Are there any limitations?

Anis Khimani (AK): Gene therapy is one of the trending therapeutic approaches to treat rare diseases. The principle behind this strategy involves understanding the gene being targeted, synthesizing a DNA or RNA to correct the mutation and creating a vehicle that will deliver the transgene to the faulty cells or tissue. With advances in this therapeutic approach, the mutation causing the disease can be corrected, which offers a therapeutic option to over half the known rare diseases.

Multiple methods of gene delivery have been explored. These include:

  • Nanoparticle-based: corrected DNA is encapsulated within lipid nanoparticles for uptake into the cells
  • Vector-based: well-characterized and studied are some viral vectors such as lentivirus or adeno-associated virus (AAV)

Critical factors that need evaluation for gene therapy to be successful include:

  • Stability of the inserted or edited gene: important to ensure that location of the gene introduction or modification does not introduce or stimulate oncogenesis or other adverse effects
  • Immune response to the carrier vectors
  • Toxicity from viral vector doses

A gene therapy approach is limited to monogenic diseases. With increased awareness of the genetics surrounding rare diseases, innovative technology solutions – for example provided by PerkinElmer – for precise identification and diagnostics, as well as gene therapy approaches to cure the disease, have fostered attention and a roadmap to address challenges.

AM: What do international multi-stakeholder collaborations mean to rare disease therapeutics?

AK: Global as well as country level initiatives such as EURORDIS have led to programs with significant funding, resulting in the establishment of centers of excellence and programs needed to study the genetic and epidemiological basis of rare disease. In addition, an increasing number of patient enrolment for clinical trials from gene- and cell-based therapies will drive a concerted effort between clinical researchers, medical care providers and recipients. Greater collaborative efforts between academia, technology innovators, therapeutic companies, regulatory agencies and non-profit organizations will lead to a unified front for rare disease. It will leverage opportunities and address challenges to unfold the next era of molecular medicine.

AM: What makes studying rare diseases challenging?

AJ: Our ability in recent years to sequence patient genomes has revealed thousands of candidate human disease variants. Establishing which variants cause which phenotypes and diseases however remains challenging since the underlying biological mechanisms of rare diseases are poorly understood.

This is further complicated as rare diseases are biologically complex and often have a singular or multifactorial genetic component that leads to many different phenotypic presentations.

Underinformed or absent biomarkers makes it challenging to identify appropriate subpopulations for a trial.

Ultimately, the lack of disease characterization and understanding novel gene-disease relationships make it challenging to provide new therapeutic options. 

AM: How are advances in technologies such as CRISPR and RNAi enabling research to further our understanding of rare diseases?

Ryan Donnelly: SNP modeling – There are some rare diseases which have a specific mutational profile. Using CRISPR-based editing to change an individual nucleotide enables the generation, and study of cell models that incorporate these mutations.

Complex cell types – Rare diseases affecting neurological and cardiovascular pathways require study of difficult-to-transfect cell types, e.g., neurons & cardiomyocytes. Optimized protocols have been developed for both RNAi and CRISPR-based methods to interrogate gene function in these types of models, ensuring that proof of principle findings are recapitulated as they move closer to the clinic.

Multiplexed manipulation – CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) enable study of complex, and rare diseases where multiple genes in a pathway are affected. These technologies allow simultaneous repression or activation of multiple genes in a single experiment.

Validation of results – RNAi and CRISPR are methods that both generate loss of function, yet they target different types of transcripts, RNA and DNA respectively. Confirming results with multiple methods ensures the strength of targets as they work their way through the drug development pipeline.


Amanda Jones, Kyoko Kushiro, Anis Khimani and Ryan Donnelly were speaking to Anna MacDonald, Science Writer for Technology Networks.

Amanda Jones is strategy leader, Life Science Research, PerkinElmer Inc.

Kyoko Kushiro is strategy leader, Academic Research, Life Sciences, PerkinElmer Inc.

Anis Khimani, PhD, is senior strategy leader Pharma Discovery, Life Sciences, PerkinElmer Inc.

Ryan Donnelly is business unit manager, Research Reagents, Horizon Discovery, A PerkinElmer Company.

In part one, find out how advances in genomic testing could help to improve the diagnostic process and what the future may hold for rare disease diagnostics.