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Chapter 18
Drug Delivery in Rare Diseases: Orphan Drugs and Therapies
Anil Kumar, Manjulendra Kumar, and Sudhir Kumar
Abstract
Nanoparticles are one of the innovative drug delivery systems, particularly valuable for the targeted delivery
of orphan drugs in rare diseases. Their nanoscale size and large surface area to volume ratio allow for
enhanced interaction with biological systems, providing a platform for efficient drug loading and controlled
release. Lipid-based nanoparticles, such as liposomes and solid lipid nanoparticles, offer biocompatibility
and stability, ensuring sustained and targeted delivery with minimal toxicity. Polymeric nanoparticles,
including dendrimers, enable the solubilization of hydrophobic drugs and precise control over drug release.
Inorganic nanoparticles, like gold and silica nanoparticles, provide versatility in functionalization and
targeted delivery, enhancing therapeutic efficacy. These systems significantly reduce systemic side effects
and improve the therapeutic index of orphan drugs, the drugs that are used to treat the rare diseases. Their
ability to protect drugs from degradation ensures stability and prolonged activity, making them particularly
suitable for complex and chronic conditions associated with rare diseases. Overall, nanoparticle-based drug
delivery systems represent a transformative approach in the treatment of rare diseases, offering precise,
controlled, and safe delivery of therapeutics, thereby improving patient outcomes and quality of life.
Key words Orphan drug challenges, Liposomal doxorubicin, Antisense oligonucleotides, Smallinterfering RNA delivery
1 Introduction
Rare diseases (RDs) are diseases that affect only a small percentage
of the population. In the United States, the Orphan Drug Act of
1983 defines an RD as one that affects fewer than 200,000 individuals [
specifically to treat these rare diseases, which often lack financial
incentives for pharmaceutical companies due to the limited patient
population. In Europe, a disease is considered rare if it affects no
more than 1 in 2000 people [
definitions, often reflecting the population size and healthcare
policy structures [3]. While each RD affects a limited number of
individuals, collectively, they affect approximately 300 million people worldwide [4]. Over 7000 RDs have been identified, with
1]. Orphan drugs are medications or treatments developed
2]. Japan and Australia have similar
407
408 Anil Kumar et al.
Table 1
Rare diseases, number of global patients, and the cost of treatment
Est. global
Rare disease Orphan drug
patients
Cost (estimated yearly)
Cystic fibrosis Kalydeco/
Ivacaftor
Duchenne muscular dystrophy Exondys
51/Etplirsen
Gaucher disease Zavesca/
Miglustat
Pompe disease Myozyme 10,000+ ~$800,000 (very high)
Hunter syndrome Elaprase/
Idursulfase
Niemann-pick disease type C Zavesca/
Miglustat
Mucopolysaccharidosis type I
(Hurler syndrome)
Spinal muscular atrophy type
1
Aldurazyme/
Laronidase
Spinraza/
Nusinersen
70,000+ ~$300,000
300,000+ ~$700,000 (high variation)
60,000+ ~$200,000 (variable)
1000+ ~$400,000 (extremely
high)
1200+ ~$400,000 (prohibitively
expensive)
1 in 100,000
births
10,000+ ~$750,000 (highest
~$500,000 (extremely
high)
for any
drug)
about 80% having genetic origins [4]. The prevalence of RDs varies
widely; some conditions may affect only a handful of individuals
globally, while others, like cystic fibrosis or Duchenne muscular
dystrophy, have higher incidence rates but still meet the rare disease
criteria [
5].
The small number of patients poses a potential lack of market
incentives, making it difficult for pharmaceutical companies to
recoup their investments (Table 1) [6, 7]. The rarity of Fabry
disease, affecting 1 in 40,000 to 1 in 60,000 males, underscores
the economic challenges in developing new therapies (Table 1) [8–
10]. The high cost of research and development, coupled with the
necessity for extensive clinical trials, exacerbates the financial burden on these companies, making the return on investment uncer-
6, 11–13]. T
tain [
he development of orphan drugs is incentivized
by various regulatory frameworks, such as the Orphan Drug Act in
the United States, which provides benefits including tax credits,
grant funding, and market exclusivity for a certain period [
14]. Sim-
ilar incentives exist in the European Union and other regions to
encourage phar maceutical companies to invest in the research and
development of treatments for rare diseases and orphan drugs [
Various
drugs (Table
drug delivery systems have been developed to deliver
2). A promising approach is the use of viral vectors in
gene therapy, which introduces functional genes to correct genetic
15].