Cabaletta for the treatment of Oculopharyngeal Muscular Dystrophy (OPMD)
OPMD is an inherited myopathy characterized by dysphagia (difficulty in swallowing) and the loss of muscular strength and weakness in multiple parts of the body. As the dysphagia becomes more severe, patients become malnourished, lose significant weight, become dehydrated and suffer from repeated incidents of aspiration pneumonia. These last two are often the cause of death. The disease is caused by genetic mutation responsible for the creation of a mutant unstable protein ( PABPN1) that aggregates within patient’s cell.
Cabaletta is chemical chaperone that protects against pathological processes in cells. It has been shown to prevent pathological aggregation of proteins within cells in several diseases associated with abnormal cellular-protein aggregation as well as acting as an autophagy enhancer. Cabaletta has been documented as demonstrating significant efficacy in preclinical animal models of OPMD and other PolyA/PolyQ diseases.
BioBlast’s current HOPEMD Phase 2/3 clinical trial is aimed at testing the efficacy of Cabaletta to treat OPMD patients.
Cabaletta for the treatment of spinocerebellar ataxia type 3 (SCA3) (Machado Joseph disease)
SCA3, also known as Machado Joseph disease, is the most common disease among the cerebellar ataxias, which are a group of genetic diseases that are characterized by memory deficits, spasticity, difficulty with speech and swallowing, weakness in arms and other muscular disorders. Symptoms can begin in early adolescence and get worse over time. In severe cases can SCA lead to an early death in the fourth decade of life. SCA3 is incurable, and there is currently no approved treatment for the disease.
SCA3 is caused by a mutation in the DNA that leads to the creation of a pathological protein – Ataxin 3. Ataxin 3 is unstable, and aggregates within the cells and eventually leads to cell death.
Cabaletta was found to be effective, both as an anti-mutant protein aggregation agent and as an autophagy enhancer, in reducing protein aggregates and improve cell survival in several spinocerebellar ataxias including SCA3 cells. Additional animal studies show that activation of autophagy may be beneficial in alleviating disease symptoms.
After concluding additional preclinical work, BioBlast is currently conducting the Phase 2 study.
Cabaletta for the treatment of Spinobulbar Muscular Atrophy (SBMA – Kennedy’s disease)
SBMA, also known as Kennedy’s disease, is characterized by the degeneration and loss of lower motor neurons in the brainstem and spinal cord. Patients suffer from weakness in muscle function, including severe difficulty in swallowing and aspiration. . SBMA is caused by an abnormal androgen receptor (AR) protein. Like other PolyA/PolyQ diseases, the abnormal protein is unstable and aggregates within cells, eventually leading to cell death. Patients suffering from SBMA suffer from progressive neuromuscular deterioration that can end up in extreme disability and repeated aspiration pneumonia. There is currently no approved therapy for SBMA.
Studies in cell models have shown that Cabaletta in its capacity both as an anti-mutant protein aggregation and as an autophagy enhancer is able to reduce protein aggregates and improve cell survival in SBMA cells. Additional studies show that activation of autophagy may be beneficial in alleviating disease symptoms in animal models.
After concluding additional preclinical work, BioBlast plan to start a Phase 2 study.
BBrm1 for the treatment of Spinal Muscular Atrophy (SMA)
SMA is the leading genetic cause of infantile death and is caused by the loss of a functional Survival Motor Neuron 1(SMN1). The disease is manifested by loss of muscle mass and mobility as well as severe compromise of vital functions such as respiration. Another protein called SMN2 is a nearly identical copy of SMN1, differentiated only by a silent, single-nucleotide mutation within the DNA. SMN2 partially compensates for the dysfunction of SMN1, however, the small amount of the functional protein that is produced from the SMN2 gene is not able to fully compensate for the loss of SMN1. Prior independent studies proposed that read-through agents, such as aminoglycosides, can induce the read-through of the stop codon located in the SMN2- protein, thus elongating the SMN2 and creating a full length functional protein that can compensate for the non-functioning SMN1 and alleviate the disease. This approach was also successfully tested in SMA animal models. Unfortunately chronic administration of aminoglycosides was found to be associated with prohibitive toxicity.
Nevertheless, drug-induced read-through of premature stop codons remains a promising approach to elevate active protein expression from the SMN2 gene which is an ideal therapeutic target as it is found in all SMA patients. Our family of repurposed FDA-approved non-glycosides molecules (BBrm) induce significantly higher levels of full length functional SMN2 protein. Using our BBrm platform, we developed a unique therapeutic candidate for SMA. We plan to continue our preclinical development of BBrm1 for SMA through 2014,and expect to start a Phase 2 study.
BB-FA for the treatment of Friedrich’s Ataxia
Friedreich’s Ataxia is an inherited disease characterized by progressive deterioration of the muscular and nervous system, resulting in gait disturbance (Ataxia), cognitive impairment, progressive heart disease and diabetes. Patients are typically diagnosed in the first or second decade of life, and are wheelchair-bound within 15 years of diagnosis. Most do not survive beyond the fourth decade of life. In many cases the cause of death is severe heart disease. The underlying causes of Friedrich’s Ataxia are reduced levels of Frataxin – a protein responsible for iron-sulphor clusters in the mitochondria that are critical for the mitochondria activity. Our preclinical data demonstrated successful placement of Frataxin into the mitochondria and in the treatment of oxidative stress in Friedreich’s Ataxia patients’ cells. We are advancing the Friedreich’s Ataxia program through its preclinical development.
BB-OTC for the treatment of ornithine transcarbamylase deficiency (OTCD)
OTCD is the most common disorder among urea cycle disorders – a group of rare genetic diseases characterized by body’s inability to detoxify ammonia. Ammonia is a toxic breakdown product of proteins. OTCD is caused by a mutated and ineffective form of the enzyme, ornithine transcarbamylase. As a result, ammonia accumulates in the blood causing hyperammonemia.
Newborn males affected with OTCD may suffer devastating hepatic coma in the first few days after birth, and survivors typically suffer from severe cognitive, mental and metabolic disorders and growth retardation. Many do not survive the first decade of life. Ornithine transcarbamylase is part of the urea cycle complex in the mitochondria. We are using our mitochondrial protein replacement platform to replace this enzyme in the mitochondria. Our preclinical data indicates that our OTC fusion protein is well able to be transferred into the mitochondria and processed in it. We are advancing the OTC program through its preclinical development.
