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Gene Therapy offers Cure for Bubble Boy Syndrome

20 Jun Gene Therapy offers Cure for Bubble Boy Syndrome

Severe combined immunodeficiency (SCID) or “Bubble Boy Syndrome” is a rare genetic disorder caused by gene mutations that inhibit the functioning of immune cells. Children afflicted with this condition are healthy in appearance but are susceptible to severe infections, even a common cold can prove fatal, so they live in isolation under constant monitoring and surveillance, leading to a very poor quality of life. X-linked severe combined immunodeficiency (XSCID) affects 1-2 infants per 100,000 births and hence is categorized as a rare genetic disorder.

This condition affects about 1 in 100,000 to 200,000 live births in the US. A report by Transparency Market Research estimates that the primary Immunodeficiency disease market will reach US $7.5 billion by 2023 growing at CAGR of 6.1%. The market was worth US $4.36 billion in 2014.

Early detection of SCID is associated with better treatment and higher survival rates. Advancements in new born screening tests now allow gene defects to be identified at the nascent stage; however in an estimated 15 percent of the cases gene defects are still unknown according to a NIH-sponsored study. X-SCID is caused by the mutation of a gene in the X chromosome and usually manifests in male infants causing abnormal growth of white blood cells and result in non-existent B-Cell functioning and a very low count of T-cells. In fact the absence of T cell receptor excision circles (TRECs) is a criterion for evaluating SCID.

Conventional treatment options are limited to hematopoietic (blood-forming) stem cell transplantation, antibiotic therapy, stem-cell transfer, gene therapy and enzyme therapy. These treatments have severe limitations as it is not easy to find a bone marrow donor or the perfect match. Transplants done within the first 3.5 months are deemed the most successful in terms of survival leaving a very narrow window of opportunity. Even then they do not restore full immunity.

Earlier attempts at using gene therapy for treating X-SCID exhibited a very alarming side effect, with patients developing leukaemia, most likely caused by the vectors that transplant cells. However, some companies have used innovative approaches to tackle this disease, with a cure now in sight.

We take a look at few companies that are focused on addressing the unmet needs in this field.

Orchard Therapeutics (NASDAQ: ORTX)

Market Cap: $1.27B; Current Share Price: 14.62 USDChart
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Orchard Therapeutics ex vivo autologous gene therapy uses stem cells collected from a patient’s body, and modified using a viral vector, carrying a functioning copy of the missing or faulty gene that are then transplanted back into the body, to correct genetic disorders.

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Its primary focus is on developing therapeutics for life-threatening inherited disorders, such as primary immune deficiencies, inherited metabolic disorders and blood disorders. Its pipeline consists of OTL-101, indicated for the treatment of ADA-SCID (adenosine deaminase severe combined immunodeficiency), which has been granted a rare pediatric disease designation and breakthrough therapy designation by the FDA.

In addition, the company is developing Strimvelis, which was acquired from GSK, for treatment of ADA-SCID. This drug has received an EMA approval in 2016, making it the first approved treatment for ADA-SCID, in the absence of a stem cell donor. It has submitted three product approvals for leukodystrophy (MLD), ADA-SCID and WAS, for which it is expecting approvals to come through by end of 2021. The company plans to file a BLA submission in the first half of 2020, followed by marketing approvals.

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The company is also developing OTL-103 for the treatment of Wiskott–Aldrich syndrome (WAS), OTL-102 for X-linked chronic granulomatous disease (or X-CGD) and other neurometabolic and hemoglobinopathies such as Metachromatic leukodystrophy (MLD), Mucopolysaccharidosis type IIIA (MPS-IIIA) and Mucopolysaccharidosis type IIIB (MPS-IIIB) to name a few.

Mustang Bio (NASDAQ: MBIO)

Market Cap: $150.28M; Current Share Price: 3.78 USDChart
Data by YChart

Mustang Bio, a clinical stage biotechnology company engaged in developing path-breaking cell and gene therapy for unmet medical needs in the fields of hematologic cancers, glioblastoma and rare genetic diseases, acquired an experimental gene through a licensing agreement in August 2018 from St. Jude Children’s Research Hospital that is now being touted as a cure for Bubble Boy Syndrome.

Mustang Bio in association with St. Jude Children’s Research Hospital has developed a safety modified lentiviral (LV) vector that is to be used in conjunction with reduced-exposure busulfan conditioning for infants afflicted by X-SCID. The addition, of low-dose busulfan not only helps ready the bone marrow for engraftment but also promotes B cell reconstitution.

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The company is presently engaged in two clinical trials. The first one is in collaboration with St.Jude’s, which is a Phase I/II gene therapy study through which 10 infants with X-SCID aged between 2 to 13 months at the time of treatment were successfully treated, with significant improvement in T cell count and B cell function. The results also show that 6 out of the 8 infants achieved reconstituted immune systems within 10 months of treatment and further 4 of the six patients did not need monthly administration of IVIG. Also no infants developed leukaemia yet as a result of the treatment.

The second clinical trial is also a Phase I/II study but for children older than 2 years which is being sponsored by National Institute of Health (NIH).

The procedure used is similar to CAR-T cell therapy, which is Mustang’s area of expertise.

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The company’s strategy is to acquire licenses for clinical CAR-T programs and Gene therapy programs that show great potential in addition to being a match to its capabilities in CAR-T processing.

In addition to MB-107, its X-SCID Gene Therapy program, it is also developing CD-123 or MB-102 and adaptive cellular immunotherapy in AML and BPDCN, a form of rare aggressive blood cancer. Its CD20 or MB-106 is an Immunotherapy program for B-Cell Non-Hodgkin Lymphoma. Additionally it is also developing CS1 or MB-104  Multiple Myeloma, IL-13Rα2 or MB-101 for the treatment of Glioblastoma (GBM), HER2 or MB-103 for Glioblastoma Multiforme, PSCA or MB-105, a prostate stem cell antigen for Prostate, Pancreatic, Gastric & Bladder Cancers and C134 or MB-108 a next-generation oncolytic herpes simplex virus (“oHSV”).

Leadiant Biosciences, Inc.

Leadiant recently received approval for Revcovi or elapegademase-lvlr, a recombinant pegylated adenosine deaminase, indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) from the FDA in 2018. Revcovi will replace the company’s legacy product AdagenⓇ, which was approved for the treatment of ADA-SCID patients, as a primary enzyme replacement therapy (ERT) in 1990. Revcovi is meant for use in bone marrow cell transplants to improve the transplant process by offering a simplified and less-invasive alternative.

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Revcovi is a PEGylated recombinant adenosine deaminase (rADA) enzyme, which needs to be administered intramuscularly, and has been formulated using a recombinant technology. This eliminates the need to source the enzyme from a cumbersome and unreliable animal source, the reason why ADAGEN had to be discontinued in the first place. It has not only helped stabilize its production process but also attain cost efficiency. The FDA approved Revcovi for the treatment of ADA-SCID in the North American market, taking its tally of rare disease products to eight.

Founded in 1980, the company was formerly known as Sigma-Tau Pharmaceuticals, Inc. and was renamed as Leadiant Biosciences, Inc. in March 2017.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

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