​More than 6,400 rare diseases impact an estimated 18 million to 30 million Americans. About 80 percent of these diseases have a genetic basis, and 50 percent affect children.

The Rare Diseases Clinical Research Network (RDCRN) consortia have examined specific rare pediatric diseases. Their research includes conditions like urea cycle disorders, Angelman, Rett, and Prader-Willi syndromes, lysosomal storage disorders, genetic disorders of mucociliary clearance, primary immune deficiencies, and mitochondrial diseases.

Advances in genomic medicine are helping researchers identify new rare diseases. Many common conditions may also reveal themselves as collections of genetic mutations. Improved clinical trial methods and study designs tailored for small sample sizes are critical in addressing rare diseases effectively.

The growing field of genomic medicine makes rare disease research in children increasingly important. Early treatment often leads to better outcomes and quality of life. For instance, in the case of phenylketonuria, early dietary therapy in infants can support normal development, while delayed treatment increases the risk of severe intellectual and physical disabilities.

​Gene therapy helps treat rare diseases by correcting genetic defects that cause the disease rather than addressing symptoms, offering the potential for long-term or curative solutions. By targeting the root cause, gene therapy aims to reduce symptom severity and frequency, decrease reliance on medications, and improve the ability to live independently.

While initial costs are high, the therapy could lower long-term healthcare expenses by reducing the need for continuous treatments and hospitalizations. Gene therapy also supports personalized medicine by tailoring treatments to specific genetic mutations. It has potential applications across many rare diseases, including cystic fibrosis, muscular dystrophy, and certain inherited forms of blindness.

Advancements in research and clinical trials continue to explore and expand the possibilities of gene therapy. Researchers must understand what happens with the body’s 25,000 genes, especially the 22,00 protein-encoding genes that express around 100,000 proteins and what the genes and proteins do and how, when, where, and in what sequence could hold the key to helping patients with rare diseases without lethal side effects. With ongoing progress, gene therapy could reshape the treatment landscape for rare diseases, bringing new options to patients.

​Genes hold the instructions that shape every cell in the body, directing the production of proteins that allow cells to grow, function, and divide. Gene therapy uses this genetic coding to address or prevent diseases by modifying these instructions within cells.

Defective genes can cause cells to produce dysfunctional proteins or prevent their production altogether, impacting normal body functions. Gene therapy aims to correct these issues, often by targeting the problem at its source. In vivo gene therapy, for example, uses viruses or tools like CRISPR (clustered regularly interspaced short palindromic repeats) within the body to modify cellular DNA directly, addressing genetic abnormalities inside cells.

Approved therapies now include gene transfer methods for high-risk, non-muscle invasive bladder cancer, delivered through an adenovirus-based approach. The FDA also approved gene therapies in 2023 for conditions caused by single-gene mutations, like sickle cell disease, using CRISPR to correct the genetic anomaly.

Researchers have developed other gene therapy techniques, such as ex vivo therapy, where they modify a patient’s immune cells outside the body before re-infusing them. Treatments like CAR T-cell therapy (for specific blood cancers), CAR NK-cell therapy (currently in trials), therapeutic cancer vaccines (like the FDA-approved prostate cancer vaccine), and oncolytic viruses (targeting advanced melanoma) genetically engineer immune cells or viruses to target cancer cells.

​Cell therapy involves transferring specific cell types into a person to address or prevent disease. Each cell type has genetic instructions determining its function and behavior. Stem cells serve as the foundation of all organs and tissues and can develop into various cell types. When disease disrupts the function of these cells, as seen in cancer, cell therapy can help by introducing healthy, functioning cells to restore balance.

Medical professionals can modify various cell types for therapeutic use in treating disorders such as blood cancers, lymphatic cancers, and plasma cell disorders. Cell therapy uses cells include “autologous” (sourced from the patient) or “allogeneic” (from a donor). Often, patients undergo conditioning pretreatment to suppress immune activity, which increases the likelihood of successful treatment.

The cells used depend on the disease and the intended treatment effect. Blood-forming stem cells (hematopoietic or HSCs) can differentiate into any blood cell needed. Immune cells can recognize and eliminate cancer cells, while mesenchymal stem cells, the most versatile stem cell type, support tissue repair based on specific needs.

Though cell therapy presents the potential for treating severe diseases, challenges remain, particularly in finding matching donors, similar to organ transplant limitations. Accuracy in directing modified cells to the correct tissues at the right volume and duration is critical. Additionally, immune suppression poses challenges, often requiring chemotherapy or other conditioning regimens to prevent an adverse immune response.

​The term “rare disease” is often used in medical contexts, but Americans may be surprised to learn that the phrase has a specific definition that has many medical and legal ramifications. In the United States, a rare disease is one impacting fewer than 200,000 individuals, or 60 per 100,000 citizens. International definitions are comparable. The European Union classes a disease as rare if it affects no more than 50 per 100,000 humans, while the World Health Organization ups that mark to 65 per 100,000 people.

While individual rare diseases impact small populations, there are a total of more than 7,000 rare diseases impacting the lives of over 30 million Americans, according to the Food and Drug Administration. As many as 300 million people around the world live with a rare disease. Examples include cystic fibrosis, hemophilia, and sickle cell.

Rare diseases are not inherently linked to one another, but they do share a few similarities. According to a 2019 paper from the European Journal of Human Genetics, an estimated 72 percent of rare diseases are genetic, while others may result from an infection or allergy.

Unfortunately, another similarity is that roughly 95 percent of rare diseases do not have a cure. However, recent decades have yielded improved awareness of rare diseases and sustained medical innovations as researchers work towards effective treatments. The US observed the first Rare Disease Day on February 28, 2008.

Sjogren-Larsson syndrome (SLS) is a rare inherited pediatric disease involving lipid metabolism. This recessive inborn error involves mutations in the enzyme ALDH3A2, which causes fatty aldehyde dehydrogenase (FALDH) deficiency. With preterm birth common in infants with SLS, it presents symptoms such as spasticity, mental retardation, and ichthyosis (dry, scaly, and itchy skin).

Most prevalent in Sweden, SLS is usually apparent at birth as ichthyosis, with neurologic symptoms manifesting in the first or second year of the infant's life. These include delays in achieving milestones such as crawling, sitting, and walking, and spasticity usually evident in the legs. Cognitive deficits are typically in the mild to moderate range and do not result in intellectual deterioration, even as children age.

The treatment for Sjogren-Larsson syndrome is mainly symptomatic and includes moisturizing lotions and keratolytic agents that help remove excess scales. Medical experts normally treat patients with spasticity using muscle relaxants, anticholinergic drugs, benzodiazepines, and physiotherapy. Researchers are currently developing genetic science approaches that target ALDH deficiency and associated metabolic defects.

​Gene therapy and cell therapy are medical procedures that share some similarities. It is not uncommon for clinical and medical teams to use both gene therapy and cell therapy terms interchangeably, but differences exist between the two procedures.

Gene therapy is a medical procedure that delivers human genetic material to fight or prevent the development of a genetic disease. Doctors harvest healthy, normal genes from one source and use them to replace missing or defective genes in another location. Doctors also may use gene therapy when disease-causing variants corrupt a protein or to increase the proteins that fight an invading pathogen.

Cell therapy on the other hand focuses on the transfer of living cells, that may or may not include genetic material. Medical professionals must source the correct cells from a donor site to replicate the same function in a different body organ. Autologous cell therapy moves cells from one location to another in the same patient, while allogeneic cell therapy uses donor cells from other healthy individuals.

​Advances in gene and cell therapy are transforming how the health sector treats and potentially cures chronic diseases. Gene therapy requires delivering the proper sequence of genes to treat, cure, or prevent a disease or medical disorder of patients who have either a defective or missing gene. As the gene or cell industry evolves, several trends - particularly in manufacturing - are worth watching as they continue to shape this therapy and its wider use.

Traditional therapeutics are often designed to treat a disease with a chronic regimen, in many instances with small molecules easy to manufacture process. However, cell and gene therapies require an innovative, often complex manufacturing process using specialized equipment and highly trained medical personnel that must genetically modify the patients' own cells. Because of that fact, before sanctioning clinical development, regulators often seek developers or sponsors with commercial-grade processes with very high quality standards to ensure patient safety.

For a long time, the application of cell and gene therapies has mainly focused on rare diseases and oncology. However, in recent years, these therapies have been increasingly used in other treatment modalities. Also, the industry has shifted the focus to other common diseases outside of cancer and also ushered in a new era for different biological therapeutics.

​A graduate of the Harvard Business School, Raj Prabhakar is a dedicated business leader who has worked in the biopharmaceutical sector for over two decades. He serves as the Chief Business Officer and Senior Vice President at Rocket Pharmaceuticals, leading all business development, partnerships, and program management. One of Raj Prabhakar's various areas of interest is rare pediatric diseases.

Adrenoleukodystrophy (ALD) is a rare pediatric disease resulting from faulty genes. According to data from ChildrensHospital.org, one in 21,000 newborn males has an ALD mutation.

ALD is inherited through a faulty gene on the X chromosome. Children who suffer from ALD have high levels of long-chain fatty acids (VLCFAs) in their brains. These fatty acids damage the myelin sheath, a protective covering on some brain cells that facilitates the cell-to-cell transfer of signals. As a result, the brain loses its ability to send signals to some body parts.

Common symptoms of ALD include poor memory, behavioral problems, difficulty reading, an inability to understand speech, and aggression. Severe symptoms from disease progression include seizures, deafness, difficulty swallowing, poor coordination, and the inability to speak. Symptoms can appear as early as the age of four. ALD typically worsens between the ages of 4 and 8 and has historically resulted in permanent disability and death during this time period.

Males with ALD genes are susceptible to the detrimental manifestations of the mutation. Less than 50 percent of females born with the genetic mutation for ALD eventually develop symptoms and complications. Early diagnosis combined with a stem cell transplant can manage ALD.

​An MBA graduate from the Harvard Business School, Raj Prabhakar is a Chief Business Officer and Head of Business Operations and Corporate Strategy at Rocket Pharmaceuticals in New York City, United States. One of the areas that Raj Prabhakar is actively involved in is preclinical and clinical development-stage operations, including Rare Pediatric Disease Designated products (RPDD).

A rare pediatric disease is a life-threatening and severe condition that affects people up to 18 years from birth and primarily manifests in newborns, neonates, infants, and adolescents. However, in order for the RPDD designation to apply, it must be rare and documented in less than 200,000 prevalence in the United States.

The RPDD attends to pediatric patients with unmet need requirements and helps stimulate research and development of new medications for RPDD through financial and tax incentives to obtain approval from the Food and Drugs Administration (FDA). The criteria to meet the RPDD includes the drug intended for someone who requires prevention or treatment of a rare pediatric disease. Also, verifiable documentation and supportive data are necessary to ensure that the intended purpose is rare and that the drug is effective.

The Food and Drug Administration Safety and Administration Innovation Act added the section in 2012 with options for priority review vouchers. To access this, however, the sponsor must request the Priority Review Voucher (PRV) in the original Non Disclosure Agreement or Biologics License Applications process.

One of the primary benefits of the RPDD is the ability of a sponsor’s eligibility to receive more benefits through an incentive program. Section 529 of the FD&C Act allows the Food and Drugs Act to award a PRV after approval for the RPDD products.