Introduction:
RD is an umbrella term used to group a road range of individual diseases that share the common trait of having a low point prevalence within a population. There are an estimated 7k forms of RD. One of the key therapeutic modalities opted for the development of new treatments for RD is gene therapy. Despite the unmet medical needs and clear rationale for gene therapy in a great many different forms of RD, the number of gene therapy products available in the clinic remains relatively low. From a specific in vivo gene therapy perspective, hundreds of clinical trails utilizing AAV based gene therapy strategies have been undertaken for a variety of indications, yet the number of in vivo gene therapies on the market is still in single digits. The case for ex vivo gene therapies is arguably better, but the nature of these medicines often limits them to rare, oncology and immunodeficiency related indications, restricting the number of RD indications with which they are applicable. Currently, as little as 5% of all RDs have pharmacological intervention options, leaving the remaining 95% with no access to established drug based treatments. One of the reasons for this disparity can be attributed to the complex commercialization models associated with developing pharmaceutical agents that target small patient populations. another problem associated with RD drug development is the lack of characterization within the diseases themselves. Of the 7k odd RDs, only 355 of them have a code in the existing International Classifcation of Diseases (ICD). (Henckaerts, “What are the issues associated with developing gene therapies for rare disease and are the current development models working?” Cell & Gene Therapy Insights 2024: 10(5), 773-784))
Ophan Drug Act (OdA): was created in an attempt to provide incentivization for the development of new drugs for RDs. The act deployed tax incentives, enhanced patent protection and marketing rights, and clinical research subsidies to spur the pharmaceutical industry into action.
Types of Rare Diseases Treated with Gene Therapy:
Alpha-1-antitrypsin deficiency: AATD is an inherited genetic disorder that affects the lungs and/or liver, leading to early onset emphysema and liver disease, and for which there are no currently approved curative treatments.
–BEAM-302 (Beam Therapeutics): is a liver-targeting lipid-nanoparticle (LNP) formulation of a guide RNA and an mRNA encoding a base editor designed to correct the disease-causing PiZ mutation. Patients homozygous for this mutation, known as the PiZZ genotype, have very low circulating levels of functional alpha-1 antitrypsin (AAT) protein, all of which is the mutant form, known as Z-AAT, which accumulates and causes liver toxicity. By correcting the PiZ mutation at the DNA level, BEAM-302 has the potential to be a one-time therapy that simultaneously reduces the amount of Z-AAT in circulation, generates therapeutic levels of corrected protein (M-AAT), and increases total and functional AAT in circulation above the 11µM protective threshold, thereby addressing the underlying pathophysiology of both the liver and lung disease. It is estimated that approximately 100,000 individuals in the U.S. have the PiZZ genotype.
BEAM-302 is a liver-targeting lipid-nanoparticle (LNP) formulation of base editing reagents designed to correct the PiZ mutation. Patients homozygous for this mutation (PiZZ) represent the majority of patients living with severe AATD disease. A one-time A-to-G correction of the PiZ mutation with Beam’s adenine base editor has the potential to simultaneously reduce the aggregation of mutant, misfolded AAT protein that causes toxicity to the liver (Z-AAT), generate therapeutic levels of corrected protein (M-AAT), and increase total and functional AAT in circulation, thereby addressing the underlying pathophysiology of both the liver and lung disease.
Following a single infusion of BEAM-302, rapid, durable, and dose-dependent increases in total AAT, new production of corrected M-AAT, and decreases in mutant Z-AAT were observed in circulation. Changes in total AAT were observed by turbidimetry assays as early as Day 7, plateaued around Day 21 and were maintained for the duration of follow-up (up to Month 6 in the 15 mg cohort, Month 2 in the 30 mg cohort, and Day 28 in the 60 mg cohort). Increased total AAT was functional as determined by both neutrophil elastase inhibition and neutrophil elastase binding assays.