Nora & Kayla's Quest for a Cure

Hi! My name is Lisa and I am the mom of 5 amazing children. Two of my children, Nora and Kayla, have been genetically diagnosed with a rare inherited bone marrow failure disorder called Shwachman-Diamond Syndrome (SDS). 

There is currently no treatment or cure for SDS. 

As a mom, that is just not something I am willing to accept. 

As a mom, I will do anything for my girls, and right now, they need and deserve a cure. 

With the help of the SDS Registry, I truly believe that we will find a cure for my girls.

What is holding us back? Funding.

Funding for rare diseases is just not where it needs to be. Rare diseases like SDS affect a much smaller community than more common ones; therefore, less funding. 
We need to change that. 
I truly believe that the SDS Registry will find us treatments and possibly a cure. Below is a summary of a project that the SDS registry is currently working on. Please consider reading about the currently project below and donating to help my sweet Nora & Kayla and others like them with SDS. 

New hope for SDSandinheritedblood disorders

Boston Children’s Hospital physician-scientists have an opportunity to drastically change how Shwachman-Diamond syndrome (SDS) and other inherited blood disorders are treated by fixing the problems at their root cause. 

Akiko Shimamura, MD, PhD, and DanielBauer, MD, PhD, propose a new platform for treating—and possibly curing—inherited blood disorders, starting with SDS. Because of SDS’s relative rarity, effecting only 1 in 80,000 newborns, the pharmaceutical investment community has largely ignored it.

There is currently no cure for SDS, and nearly 5% of children with the condition will develop leukemia, with the risk rising to 25% by adulthood. The only available definitive therapy is bone marrow transplant, which requires intense chemotherapy and carries grave risks. 

Drs. Shimamura and Bauer—who was instrumental in finding a cure for sickle cell—believe a similar curative treatment can be found using technology known as CRISPR prime editing, today’s most advanced gene-editing method. Prime editing enables scientists to use a copy-and-paste technique in which they remove one of agene’s mutated strands and replace it with a corrected sequence. It is more precise than traditional CRISPR-Cas9 editing. 

If CRISPR prime editing works in SDS, Drs. Shimamura and Bauer they can apply the technique to a host of other inheritable blood diseases.

The Blood Disorder ResearchFund at Boston Children’s Hospital needs to raise $2 million to enable Drs. Shimamura and Bauer to develop a prime-editing therapy in the lab—a step needed to initiate the first clinical trial of a potentially curative SDS therapy. In doing so, they will create a platform to develop potential cures for other devastating heritable blood diseases, including those that, despite their severity and early onset, remain unlikely targets for commercial development.

An anonymous donor from South Florida has made a leadership commitment and seeded the fund with a $250,000 donation.

The first step is to develop a prime-editing therapy in the lab. SDS is the ideal blood disorder to test the gene-editing platform for two reasons: First, nearly all cases involve the same genetic mutation. This homogeneity, a relative rarity for heritable diseases, would allow them to streamline SDS gene editing and design a universal curative SDS therapy. Second, unlike other blood disorders like sickle cell disease and leukemia, this SDS gene treatment would not require preparatory toxic chemotherapy to clear existing stem cells from bone marrow. This alternative makes treatment easier for the patient—and the clinical trial process nimbler.

 Drs. Shimamura and Bauer now need to:

• conduct the proof-of-concept studies, including the development of mouse models.

• develop off-target assays to test gene editing specificity and precision.

• conduct the preclinical safety and manufacturing studies needed to file an investigational new drug (IND) application with the FDA.

• advance the SDS Registry, founded by Dr. Shimamura, to collect crucial natural history data, define relevant biomarkers to follow the disease, and develop molecular assays—activities required to take innovative therapy from the bench to the bedside. Through the SDS Registry, Dr. Shimamura’s lab has been collecting blood and bone marrow samples from patients with SDS for more than 20 years.

• create a technology platform and infrastructure to extend cures to other blood disorders.

Drs. Shimamura and Bauer will tap the knowledge gained from the in vitro tests and use human blood cells collected from patients with SDS via the SDS Registry to conduct the proof-of-concept and subsequent preclinical studies.They will introduce SDS patient cells, with and without CRISPR prime editing, into mice. By comparing theperformance of the different cells in recipient mice, theywill investigate how gene-corrected (CRISPR prime edited) cells renew stem and progenitor cells and differentiate into mature blood cells, relative to un-edited SDS and healthy blood stem cells.

Developing off-target assays

In addition to determining the essential effectiveness of the gene-editing method to renew stem and progenitor cells, the scientists must also ensure it is sufficiently specific to the targeted site and safe. Drs. Shimamura and Bauer will conduct off-target studies, using powerful bioinformatic software tools and biochemical assays in vitro and in cells to identify any unexpected side effects of the gene editing method that could have harmful consequences throughout the genome. Because CRISPR prime editing technology is new and has not yet been tested in humans, such analyses are essential—and will be expected by the FDA—for advancing therapeutic genome editing to the clinic. Drs. Shimamura and Baueranticipate conducting about 10 different off-target assay studies.

Conducting safety andmanufacturingstudies

Once Drs. Shimamura and Bauer have shown that the SDS gene therapy is effective in the lab, they can apply to the FDA for approval to run clinical trials.

Manufacturing development to scale up the gene-editing process to human doses would initially take place in Boston Children’s TransLab, an innovative clinical and translational platform that bridges scientific discovery and clinical practice. The large-scale gene therapymanufacturing process will then be transferred to the Connell and O'Reilly Families Cell Manipulation Core Facility at the Dana-Farber Cancer Institute, to conduct gene therapy manufacturing test runs using good manufacturing practices, required when products are made for use in humans.

Creating a platform to address other blood disorders

By successfully treating SDS, Drs. Shimamura and Bauer believe they can prove the efficacy of CRISPR prime editing and apply lessons learned to treat other, rare severe genetic disorders with unmet clinical need—in essence, create a reusable gene-editing platform for inherited blood disorders.

Such a platform would be built upon this initial effort andinclude:

• therapeutic genetic material and reagents. These include cell culture and other reagents, can be copied for future blood disorder research.

• evaluationtechnologies. Most of the technologies and strategies used to assess preclinical safety and efficacy, off-target determination, manufacturingsuccess, and clinical trial design, could be readily adapted for numerous other blood disorder therapies.

• laboratory processes. These include the CRISPR prime editing technique and the attendant order of operations, only slightly modified for the next gene therapy, and the method for scale up.

• personnel. The scientific, manufacturing, regulatory and clinical know-how to flawlessly execute requires a team including scientists, project managers, and nurses, with unique skills, knowledge, and experience.

• next-generation technologies. Prime-editingstrategies that enable pharmacological selection of gene-edited blood cells not requiring chemotherapy could enhance the efficiency of replacing a diseased blood system with a healthy one for SDS and many other blood disorders.

Creation of this platform could form the basis for treating a wide range of diseases with unmet need at their root cause, ease suffering and save lives.

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