Protein Replacement Therapy for Rare Disease

Protein Replacement Therapy (PRT) is an innovative approach in rare diseases that addresses the missing protein in patients suffering from rare conditions.

Rare diseases, often referred to as orphan diseases, are medical conditions that affect a small percentage of the population, typically fewer than 200,000 individuals in the United States and an almost equivalent number in other countries. These are often genetic, but can also result from infections, environmental factors, or any unknown causes. One of the most significant challenges in dealing with rare diseases is their lack of treatment options. Due to rarity, research and development efforts tend to be limited, and less knowledge of disorder pathways makes it difficult to attract funding and resources for drug development.

However, there is hope on the horizon for individuals with rare diseases through protein replacement therapy (PRT). This innovative approach involves providing patients with specific proteins they are missing or producing in insufficient quantity. Recently for the treatment of Pompe disease, patients receiving specific doses of recombinant human alglucosidase alfa have shown great results during the treatment.

Why Protein as an Alternative Therapeutic Approach?

• Lesser Side Effects – The action of modified protein is very precise with fewer opportunities for protein treatments to interfere with normal biological processes and fewer unwanted consequences.
• Advantages over gene therapy – Protein therapeutics can provide effective replacement therapy without interfering with the genetic makeup, which is currently not available for most genetic disorders.
• Easier approvals – Clinical development and FDA approval for protein therapeutics may be faster than that of small molecule drugs.
• Protection from degradation – Protein degradation is ignored if the ubiquitination tag on the protein is removed.
• Target-specific binding – Protein therapeutics offer a higher target approach and may have fewer off-target effects compared to traditional small molecule drugs.

Ways to Develop Protein Replacement Therapy

• Gene Therapy – Thisproduces therapeutic proteins by inserting the desired gene into host cells, enabling them to synthesize the protein, addressing genetic disorders or deficiencies in patients.
• Protein engineering – It tailors proteins to replace or augment deficient ones in a therapeutic approach, enhancing their stability, specificity, and efficacy, benefiting patients with various diseases, including enzyme deficiencies.
• Transgenic animals – They are engineered to produce therapeutic proteins such as insulin, and serve as bioreactors for cost-effective protein replacement therapy production.
• Nanotechnology – Thisaids protein replacement therapy by designing nanoparticles to deliver therapeutic proteins, enhancing their stability and targeted delivery, improving treatment efficacy, and reducing side effects.

Enzyme Replacement Therapy

ERT is a therapeutic approach wherein a specific enzyme that is absent or inactive in infected individuals is replaced with a functional enzyme molecule. One of the many rare diseases due to dysfunctional enzymes is Lysosomal storage disorder (LSD), a genetically rare condition brought on by an accumulation of toxic materials in the body’s cells. Also, this results in various disorders like Hunter’s syndrome, Fabry’s disease, and many more, wherein certain enzymes or substances that act as activators or modifiers of the enzyme activity, are absent. The replacement of these enzymes can help biological processes return to normal.

mRNA-based Protein Replacement Therapy

mRNA-based pharmaceuticals have emerged as an effective solution. They also produce proteins in vivo, and use the patient’s cellular machinery to synthesize the required protein. Moreover, this avoids the difficulties involved in the external production and purification of protein. mRNA-based therapies being utilized these days for specific rare diseases involve –

• Acute Intermittent Porphyria – Moderna is developing a mRNA-based therapy for acute intermittent porphyria (caused by the deficiency of hydroxymethylbilane synthase) by delivering human PBGD mRNA (encoded for the gene HMBS), coated in lipid nanoparticles.
• Hemophilia A – LNPs carrying mRNAs encoding different variants of human FVIII (F8 LNPs) used to treat Hemophilia A are being developed by Moderna along with the University of Washington.
• Cystic Fibrosis – Translate Bio/Sanofi developed MRT5005, a drug designed to restore CFTR function by delivering correct copies of CFTR-encoded mRNA to the lungs.

Recent Commercial Trends

Clinical Trials

Many companies are trying to develop therapies for different rare diseases through protein replacement. A few of the current approaches are explained below –

• Moderna – mRNA-3927 is under Phase II of the trial, wherein it encodes two subunit proteins, PCCA and PCCB, in patients for treating Propionic Acidemia.
• Larimar Therapeutics – CTI1601, a recombinant fusion protein, designed to transport human frataxin into the mitochondria of individuals suffering from Friedreich’s ataxia is currently under Phase II of clinical trials.