14 May LogicBio Therapeutics: Potential breakthrough in the Treatment of Methylmalonic Acidemia (MMA).
LogicBio Therapeutics (NASDAQ: LOGC), a gene-editing company that uses its GeneRide technology platform to develop solutions for rare diseases in pediatric patients was recently awarded an Orphan Drug Designation (ODD) status for its LB-001 a recombinant adeno-associated viral vector with human methylmalonyl-COA mutase (MUT) gene for the treatment of methylmalonic acidemia (MMA).
LB-001 developed using a proprietary promoterless, nuclease-free genome editing platform is likely to be filed for an Investigational New Drug License (IND) by the company in Q4,2019 with plans to start a Phase I/II clinical trial in 2020.
Addressing Unmet Needs in Methylmalonic Acidemia
Methylmalonic Academia, a rare inherited disease that occurs in an estimated 1 in 50,000 to 100,000 people, is characterized by the inability of the body to process proteins and lipids effectively. This disease mostly affects infants leading to hypotonia, hepatomegaly and in severe cases failure to thrive. It also has several long-term complications such as developmental disability, chronic kidney disease and pancreatitis that can lead to death if left untreated.
This disorder is caused due to mutations in the MMUT, MMAA, MMAB, MMADHC, and MCEE genes which also determine its severity and long-term implications. However, MMUT gene is the leading cause of the disease with over 60% of the cases being attributed to its malfunctioning. This gene is responsible for producing the enzyme named methylmalonyl CoA mutase which interacts with vitamin B12 (cobalamin) to break down amino acids, lipids and cholesterol. Mutations in this gene can inhibit the production of this enzyme leading to accumulation of methylmalonyl CoA and other toxinc compounds in vital organs.
In severe cases, no functional enzymes are produced leading to a condition called mut0 that has very poor outcomes. This disease follows an autosomal recessive pattern, with the parents acting as carriers of one copy of the mutated gene. An elevated C3 acylcarnitine is one of the indicators of this disease, other methods of diagnosis use genetic testing as well.
Limitations of Conventional Treatment Options
New born screening is recommended and takes into account the final diagnosis in an infant with a positive newborn screening result. Owing to the extremely rare nature of this disease there are chances of a delayed diagnosis owing to very low awareness levels about this condition. methylmalonic acidemia usually starts manifesting when proteins are added to the diet during the first year of birth.
The current treatment approach is a low-protein, high-calorie diet that limits the intake of isoleucine, threonine, methionine, and valine with inclusion of supplements to treat carnitine deficiency. Cyanocobalamin supplements are the first line of treatment of this disorder although their efficacy in treating some forms of methylmalonyl acidemia is severely limited. Cobalamin (vitamin B12) injections and antibiotics are also used for treating certain cases. In extreme situations organ transplantations may be carried out and the donor organ may be able to produce a functional version of methylmalonic-CoA and aid its metabolism.
Those suffering from cobalamin-responsive variants show a better prognosis than those suffering from noncobalamin-responsive variants. No cure exists for the disorder as yet however recent scientific advancements along with increased research and development efforts have improved the life expectancy and quality of life of those affected.
LogicBio’s Therapeutic Approach and Pipeline
GeneRide, the company’s genome editing platform aims at creating long-lasting solutions for unmet medical needs through a single injection. It uses the natural DNA repair process, known as homologous recombination of natural cells to introduce transgene at a predetermined spot to the nuclei of the patient’s cells via an infusion. Currently it is using Stanford University’s library of synthetic, non-pathogenic, AAV vectors for its liver program.
This technology offers numerous advantages over traditional therapeutic approaches; firstly by introducing the corrective gene into the patient’s genome at a precise point, it becomes an intergral part of the DNA and leads to a more durable effect something that the conventional gene therapy does not offer.
Secondly, its platform is independent of exogenous (foreign) nucleases which reduce the risk of off-target cuts and fatal changes to the patient’s chromosomes. Since they do not use bacteria derived nucleases they eliminate the risk of provoking a strong defense by immune system and genotoxicities.
The third and most important advantage is that by eliminating the use of exogenous promoters which can change the expression of other genes including oncogenes, it reduces the risk of cancer and other genotoxicities.
LB-001 is a GeneRide vector for pediatric patients who suffer from methylmalonic acidemia (MMA), which has demonstrated the ability to improve protein tolerance and growth and reduce toxic metabolites in mice during clinical studies. LB-can integrate a functioning version of the malfunctioning MUT gene into the genome of patients thereby offering a survival advantage over cells not expressing the transgene.
Its pipeline is at present focused on making innovative solutions for liver ailments such as Hemophilia B, AIATD and Crigler-Najjar with plans to extend the line to include Muscle and Central nervous system related disorders.
We believe that the company will fully utilize the opportunity presented by the granting of an Orphan Drug Designation (ODD) to further its clinical pipeline to include other ailments that could benefit from its GeneRide technology platform. The company is likely to file for an Investigational New Drug (IND) license application with the FDA in Q4 for 2019 and intends to start a Phase I/II clinical trial in 2020, given the positive outcome from its pre-clinical studies in mice, it looks all set successfully complete the trials in humans as well.
Owing to the rare nature and limited treatment options for the disease, any breakthrough treatment plan is likely to be accepted quickly by patients and medical practitioners alike, which could work in LogicBio’s favour.
LogicBio, founded in 2014 and head quartered in Massachusetts, is engaged in developing vectors based on non-pathogenic Adeno-Associated Viral (AAV) using its proprietary GeneRide platform for rare genetic and infectious diseases such as methylmalonic acidemia (MMA), haemophilia and HIV/AIDS. Its path-breaking technology offers an improvement over conventional gene therapies by integrating modified genes to replace malfunctioning genes into a patient’s genome without causing any peripheral damage and providing extended therapeutic durations.
Its technology is based on the work of Mark Kay, M.D., Ph.D., Adi Barzel, Ph.D., and Leszek Lisowski, Ph.D., MBA, the Company’s scientific advisers and global leaders in gene therapy and gene editing.
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