Researchers can help to market the cures for cancer and retinoblastoma

Simplifying CAR-T therapies for people with rare conditions, including Alzheimer’s disease: A sprint to a cure for cancer and other diseases

Researchers are trying to make the process simpler. Doudna’s institute, for example, is working to standardize some aspects of genome-editing therapies, in part to make it cheaper and easier to develop such treatments for people with rare conditions. The US National Institute of Health is trying to create a similar process for developing new gene therapies. “It’s been really hard,” says Doudna. What we are doing is going to have long-term impact.

Today, the chatter is very different. More than 30,000 people with cancer in the United States have been treated with engineered CAR T immune cells. CAR-T therapy is being tested for other conditions, including some severe autoimmune disorders. CAR T cells earned US$8.4 billion for the companies that made them.

Challenges exist for both approaches. CAR-T therapy’s early days are similar to what we’re seeing today. But by guiding regulators and developing flexible platforms for producing bespoke treatments, researchers can help to shepherd therapies to the people who need them.

Vaccines could rally the immune system against tumours, similar to how vaccines rouse the defences against pathogens. Companies can now sequence portions of a person’s tumour and select those most likely to be visible to the immune system. The mRNA molecules corresponding to those regions are synthesized, then encapsulated in fatty particles and injected — much like mRNA COVID-19 vaccines. From start to finish, the process takes as little as a month.

In theory, many people with a genetic condition, no matter how rare, could benefit from these technologies. But the reality is harsher. It will take years for techniques to be developed that will allow for quick, on-demand therapies. Most people with these conditions are not able to do that in a lot of time.

Ghosh and his collaborators were racing to design a one-off treatment that would edit the DNA in the 20-year-old woman’s brain cells and get them to stop producing toxic proteins. It was an approach that had never been tried before, with a long list of reasons for why it might not work.

But Uditi’s family could not wait — the pace of scientific research was too slow. They needed a quick sprint and a group of researchers willing to try something that hadn’t been done before. The thing that we were attempting to do was almost in the realm of science fiction.

There is still a lot of groundwork being laid for this future. They are working out how best to design and manufacture the treatments, and how to deliver them to precise locations in the body. The cost of genome-editing therapy is a serious problem because it is out of reach for many. He feels that India will eventually be able to bring those barriers down, since he sees them as the country to do it.

How the Sarafs of India don’t know their brain is FENIB: their teenage daughter explains to her mother that she has Alzheimer’s disease

As a young girl, Uditi was always in a hurry. She would buzz around the house getting ready hours ahead of everyone else so she could make sure she had everything ready for the party. She welcomed family and friends with hugs, kisses and laughter.

There was no sign of trouble for the first nine years. And when it began, it was just a flicker — a few seconds here and there, when Uditi would zone out.

She’d switch back on again as if nothing had happened, and her mother, Sonam, wasn’t sure if she should worry. But then Sonam saw nine-year-old Uditi drop a camera on the floor and become confused as to why it was no longer in her hand. A mother’s hunch hardened: something was wrong.

The physicians diagnosed her with epilepsy. The father and mother of Uditi decided it must be something more after she began to have convulsions at school. They had part of Uditi’s genome analyzed in 2017).

It was a deviation from the standard treatment path, but the Sarafs were technologically savvy and financially well off. In India, as in many places in the world, genome sequencing was still uncommon, its roll-out slowed both by the costs and by the dearth of genetic information from people of Indian descent in genetic databases. It can be difficult to interpret the results without such data.

Uditi’s results, however, were unambiguous: a single-base change in the gene that codes for a protein called neuroserpin caused tangled polymers to form in her brain cells, interfering with their function. Uditi had dying cells in her brain.

This condition is called FENIB (familial encephalopathy with neuroserpin inclusion bodies), and the symptoms — which can be similar to dementia — usually manifest late in life. Elena Miranda, a cell biologist at the Sapienza University of Rome, runs the world’s only lab that focuses on the disease. She believes that many elderly people with dementia may not know they have FENIB because physicians don’t always sequence their genomes.

Uditi and her parents embarked on a lonely journey familiar to many people with rare diseases. They had never heard of Uditi’s physicians. Sonam did some research but was not able to fully absorb what she found. “We thought it’s not possible,” she says. Our daughter cannot do that.

Uditi’s disease was caused by a mutation that converts a single DNA base from a ‘G’ to an ‘A’. A variation on CRISPR genome editing, called base editing, could theoretically correct exactly this kind of mutation (see ‘Precision gene repair’).

Devinsky also emphasized the difficulties. At that time, base editing — which was first reported in 2016 — had never been tested in a clinical trial. The technique is reliant on shuttling a largeprotein and a smallRNA into affected cells. The brain is one of the most difficult to deliver for many organs, and researchers were struggling with how to perfect it.

Devinsky assembled a team at NYU Langone Health with expertise in genome editing and neuroscience to conduct preliminary studies of the approach. The researchers gathered funding from other grants and the Sarafs funded the rest. “We will sell our house if we have to,” Sonam said.

The work continues in India. Rajeev has urged Chakraborty to finish the team’s studies in mice, so that the next person with FENIB will not have to wait as long for a potential treatment. Some of the work will be completed, and the effort could benefit others with genetic conditions that affect the brain — particularly in India. He says they are not trying as hard as before. “But that technology has a lot of potential.”

In December of last year, the Sarafs moved to India. Uditi missed her family while she lived in the United States. Then the COVID-19 pandemic struck, and in January 2021, Uditi was hospitalized with severe COVID-19. She spent 20 days in the hospital and her health was never the same, says Sonam. Communication became increasingly difficult for Uditi and she began to pace the house incessantly, rarely even going to sleep.

A different treatment called antisense therapy was petitioned for by the US foundation. The family flew from India to the United States twice for injections into her spine. The trips became traumatic as her ability to understand the world around her declined.

When nine-year-old Uditi first dropped her camera, CRISPR was just an oddity — a strange assembly of sequences found in microbial genomes, only studied by a few die-hard microbiologists. Four years before she was diagnosed with FENIB, researchers showed for the first time that a CRISPR-based system could cut DNA in human cells grown in the lab. Uditi died and the United Kingdom approved genome-editing therapy to treat her disease within a month.

Most of the people with sickle-cell disease in India — a country with one of the highest rates of the condition — live in impoverished communities. They hoped to develop a therapy that could be administered at a fraction of the price charged in the United States.

Source: Hope, despair and CRISPR — the race to save one woman’s life

The India Project to Identify the Causes of Duchenne Mdds, and the Challenge to Save a Woman’s Life

Still, that was not the end of their challenges. The genes needed in base editing are longer in AAV genomes, but they only carry an extra 4,700 DNA bases. Ghosh and his students worked to divide up their genomic cargo so that it could fit in two separate viruses, and added sequences that would allow the two pieces to be spliced together again when they are expressed inside a cell. The team would inject the viruses at the same time.

It was not the first time Ghosh was swayed by a personal appeal: a few years before he met Uditi, Ghosh came to work and found two women waiting outside of his office. They would not leave, the women said, until he committed to finding a treatment for their young sons’ illness, a genetic condition called Duchenne muscular dystrophy, which can be fatal. The women promised to help raise money, and Ghosh was not able to say no. He has been close to the families since working on the project.

India has earned a reputation for making complex drugs on a budget. During the COVID-19 pandemic, Indian manufacturers cranked out millions of doses of vaccines. Now, the country is manufacturing a malaria vaccine at a fraction of the cost of that in Europe, and it is developing sophisticated cell and gene therapies used in cancer treatments for much less than the price of those in the United States.

Source: Hope, despair and CRISPR — the race to save one woman’s life

Getting AAV9 in the Brain: A Collaboration Project for Uditi’s Neuronal Therapy and Brain Structural Studies

Chakraborty took the lead on Uditi’s project. Riya Rauthan was a PhD student in the lab and she says that he is a go-getter. He doesn’t care who he asks to get something done, he does it.

To minimize interruptions, the team mapped out all of the experiments and the components they would need from start to finish. Lab reagent imports and supply disruptions can cause projects to be put on hold for weeks or months. Maiti was able to keep the supplies coming and negotiate prices with vendors because she was ordered ahead of time. He says that time was more valuable than anything else.

Stem cells were derived from Uditi’s blood. Then, she and her colleagues coaxed those cells to become neurons, and used base editing on them in the lab.

The AAV that would be used to transport the components into the Uditi’s cells was prepared by Ghosh. The team needed to determine which strain of AAV would work best — some strains could trigger inflammation in the brain. To find out which AAV caused the least amount of inflammation, the lab tested several types in mice. After a lot of consideration the team decided that it was appropriate to inject AAV9 directly into Uditi’s brain.

The news was hard for those in the lab. “For clinicians, perhaps they become hardened,” says Chakraborty. “We don’t have that experience. We were feeling agony.”

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